JP2023550793A - Fused tricyclic compounds, their preparation methods and their pharmaceutical applications - Google Patents

Abstract

The present disclosure relates to fused tricyclic compounds, methods of their preparation and their pharmaceutical applications. Specifically, the present disclosure provides a fused tricyclic compound represented by general formula (I), a method for its preparation and a pharmaceutical composition comprising the compound, and its use as a therapeutic agent, particularly as a TLR7/8/9 inhibitor. and in the preparation of medicaments for the treatment and/or prevention of inflammatory and autoimmune diseases. The definition of each group in general formula (I) is as defined in the specification. JPEG2023550793000119.jpg37170

Description

The present disclosure belongs to the pharmaceutical field and relates to fused tricyclic compounds, their preparation methods and their pharmaceutical applications. In particular, the present disclosure provides fused tricyclic compounds of general formula (I), methods for their preparation and pharmaceutical compositions containing the compounds, and their use as therapeutic agents, particularly as TLR7/8/9 inhibitors. and use in the preparation of medicaments for the treatment and/or prevention of inflammatory and autoimmune diseases.

Toll-like receptors (TLRs) are evolutionarily conserved transmembrane innate immune receptors that are involved in the first line of defense to protect human health and are associated with pathogen-associated molecular patterns (PAMPs). ) (Kawai, T. et al., Nature Immunol., 11, 2010, 373-384). TLRs are expressed in various immune cells, and depending on their expression site, there are TLRs expressed in the cell membrane (TLR1/2/4/5/6) and TLRs expressed in the endosomal membrane (TLR3/7/8/9). They are divided into two types, each recognizing different components and molecules in PAMP. Among them, TLR7/8/9 is highly expressed mainly in DC cells and B cells, TLR7/8 mainly recognizes ssRNA, and TLR9 mainly recognizes CpG-DNA. TLR7/8/9 is activated after binding to its ligand and binds to the adapter protein MyD88 in the cytoplasm, initiating the NF-κB and IRF pathways, activating DC cells, and promoting type I interferon and other various inflammation produces sexual cytokines. In B cells, TLR7/8/9 plays an important role in the production of antinuclear antibodies by B cells after binding with nucleic acids, and type I interferon secreted from DC cells also plays an important role in the production of antinuclear antibodies by B cells. Promoting further proliferation and activation of B cells, it triggers a series of inflammatory responses.

Systemic lupus erythematosus (SLE) belongs to autoimmune connective tissue diseases, and the clinical first-line drugs for SLE are of three types: hormones, immune inhibitors, and antimalarial drugs. Only one new drug, belimumab, has been approved by the FDA this century, but it has modest, delayed therapeutic effects in only a small proportion of SLE patients (Navarra, S. V., et al., Lancet 2011, 377). , 721), treatment options are very limited. Therefore, new treatments that improve a larger proportion of the patient population and are safe for long-term use are desperately needed. It was observed that the expression of TLR7/9 and type I interferon was significantly upregulated in PBMC of systemic lupus erythematosus (SLE) patients (Beverly D.LC, et al., Mol Immunol., 2014, 61:38-43). Reports indicate that mice overexpressing TLR7 can exacerbate autoimmune diseases and autoinflammation (Santiago-Raber ML, et al., J Immunol., 2008, 181:1556-1562); Functional inhibition of /9 can alleviate the pathological symptoms of lupus mice such as B6-Fas ^lpr and BXSB (Dwight H. Kono, et al., PNAS, 2009, 106(29): 12061-12066 ). In view of the close relationship between TLR7/8/9 and antinuclear antibodies and type I interferon, small molecule inhibitors targeting TLR7/8/9 have great potential to treat SLE.

Patent applications for disclosed TLR7/8/9 inhibitors include WO2019233941A1, WO2020020800 A1, WO2018049089A1, WO2017106607A1, CN109923108A, WO2020048605A1, and others.

The present disclosure aims to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
One of these days,
Y is CR ^4a or a nitrogen atom,
Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
R ⁰ is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR ^g R ^L , nitro group, hydroxy group, hydroxyalkyl group as well as
Among them, the alkyl group is optionally an alkoxy group, a haloalkoxy group, a cyano group, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , a cycloalkyl group, a heterocyclyl group, an aryl group. and one or more substituents selected from heteroaryl groups,
L is selected from a chemical bond, NR ^L , an oxygen atom, a sulfur atom, and an alkylene group, where the alkylene group is optionally a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy substituted with one or more substituents selected from groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups,
R ^g and R ^L are the same or different, and each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. selected from
Ring C is selected from a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
Each R ¹ is the same or different, and each independently represents a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the above-mentioned alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and Heteroaryl groups each independently optionally include halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, Substituted with one or more substituents selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
^R2 is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group , aryl group, and heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with halogen. , alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group substituted with one or more selected substituents,
^R3 is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group , aryl group, and heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with halogen. , alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group substituted with one or more selected substituents,
Each R ⁴ is the same or different, and each independently represents a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an oxo group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group , nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the above alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, Aryl and heteroaryl groups each independently optionally include halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxy group. Substituted with one or more substituents selected from an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
R ^4a is selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, and a hydroxyalkyl group,
Each R ⁵ is the same or different, and each independently represents a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, oxo group, haloalkyl group, haloalkoxy group, cyano group, amino group , -NR ^c R ^d , selected from nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the above-mentioned alkyl group, alkenyl group, alkynyl group, alkoxy group, cyclo Alkyl, heterocyclyl, aryl and heteroaryl groups each independently optionally include halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino group, nitro group, hydroxy group, hydroxyalkyl group, -C(O)OR ⁶ , -C(O)NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(O) ₂ R ⁹ , cycloalkyl group, heterocyclyl substituted with one or more substituents selected from groups, aryl groups and heteroaryl groups,
R ⁶ is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
R ^c , R ^d , R ⁷ and R ⁸ are the same or different, and each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group , aryl group and heteroaryl group,
Alternatively, R ^c and R ^d together with the linked nitrogen atom form a heterocyclyl group, and the heterocyclyl group optionally includes a halogen, an alkyl group, an oxo group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, Substituted with one or more substituents selected from a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
Alternatively, R ⁷ and R ⁸ together with the linked nitrogen atom form a heterocyclyl group, and the heterocyclyl group optionally includes a halogen, an alkyl group, an oxo group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, Substituted with one or more substituents selected from a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
^R9 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
J is 0, 1 or 2,
k is 0, 1 or 2,
n is 0, 1, 2, 3 or 4,
s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof,
Y is CR ^4a or a nitrogen atom,
Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
R ⁰ is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR ^g R ^L , nitro group, hydroxy group, hydroxyalkyl group as well as
selected from
L is selected from a chemical bond, NR ^L , an oxygen atom, a sulfur atom, and an alkylene group, where the alkylene group is optionally a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy substituted with one or more substituents selected from groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups,
R ^g and R ^L are the same or different, and each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. selected from
Ring C is selected from a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
Each R ¹ is the same or different, and each independently represents a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the above-mentioned alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and Heteroaryl groups each independently optionally include halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, Substituted with one or more substituents selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
^R2 is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group , aryl group, and heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with halogen. , alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group substituted with one or more selected substituents,
^R3 is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group , aryl group, and heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with halogen. , alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group substituted with one or more selected substituents,
Each R ⁴ is the same or different, and each independently represents a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an oxo group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group , nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the above alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, Aryl and heteroaryl groups each independently optionally include halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxy group. Substituted with one or more substituents selected from an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
R ^4a is selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, and a hydroxyalkyl group,
Each R ⁵ is the same or different, and each independently represents a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, oxo group, haloalkyl group, haloalkoxy group, cyano group, amino group , -NR ^c R ^d , selected from nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the above-mentioned alkyl group, alkenyl group, alkynyl group, alkoxy group, cyclo Alkyl, heterocyclyl, aryl and heteroaryl groups each independently optionally include halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino group, nitro group, hydroxy group, hydroxyalkyl group, -C(O)OR ⁶ , -C(O)NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(O) ₂ R ⁹ , cycloalkyl group, heterocyclyl substituted with one or more substituents selected from groups, aryl groups and heteroaryl groups,
R ⁶ is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
R ^c , R ^d , R ⁷ and R ⁸ are the same or different, and each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group , aryl group and heteroaryl group,
Alternatively, R ^c and R ^d together with the linked nitrogen atom form a heterocyclyl group, and the heterocyclyl group optionally includes a halogen, an alkyl group, an oxo group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, Substituted with one or more substituents selected from a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
Alternatively, R ⁷ and R ⁸ together with the linked nitrogen atom form a heterocyclyl group, and the heterocyclyl group optionally includes a halogen, an alkyl group, an oxo group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, Substituted with one or more substituents selected from a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
^R9 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
J is 0, 1 or 2,
k is 0, 1 or 2,
n is 0, 1, 2, 3 or 4,
s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof,
Y is CR ^4a or a nitrogen atom,
Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
R ⁰ is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR ^g R ^L , nitro group, hydroxy group, hydroxyalkyl group as well as
selected from
L is selected from a chemical bond, NR ^L , an oxygen atom, a sulfur atom, and an alkylene group, where the alkylene group is optionally a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy substituted with one or more substituents selected from groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups,
R ^g and R ^L are the same or different, and each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. selected from
Ring C is selected from a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
Each R ¹ is the same or different, and each independently represents a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the above-mentioned alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and Heteroaryl groups each independently optionally include halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, Substituted with one or more substituents selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
^R2 is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group , aryl group, and heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with halogen. , alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group substituted with one or more selected substituents,
^R3 is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group , aryl group, and heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with halogen. , alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group substituted with one or more selected substituents,
Each R ⁴ is the same or different, and each independently represents a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an oxo group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group , nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the above alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, Aryl and heteroaryl groups each independently optionally include halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxy group. Substituted with one or more substituents selected from an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
R ^4a is selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, and a hydroxyalkyl group,
Each R ⁵ is the same or different, and each independently represents a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, oxo group, haloalkyl group, haloalkoxy group, cyano group, amino group , nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the above alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, Aryl and heteroaryl groups each independently optionally include halogen, alkyl group, oxo group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group. group, hydroxyalkyl group, -C(O)OR ⁶ , -C(O)NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(O) ₂ R ⁹ , cycloalkyl group, heterocyclyl group, aryl group and hetero substituted with one or more substituents selected from aryl groups,
R ⁶ is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
R ⁷ and R ⁸ are the same or different, and each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. selected from
Alternatively, R ⁷ and R ⁸ together with the linked nitrogen atom form a heterocyclyl group, and the heterocyclyl group optionally includes a halogen, an alkyl group, an oxo group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, Substituted with one or more substituents selected from a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
^R9 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
J is 0, 1 or 2,
k is 0, 1 or 2,
n is 0, 1, 2, 3 or 4,
s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, in which each R ⁵ is homologous or different, and Each independently represents a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, oxo group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group , heterocyclyl group, aryl group, and heteroaryl group, among which each of the above alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently selected. halogen, alkyl group, oxo group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, -C(O)OR ⁶ , Substituted with one or more substituents selected from -C(O)NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(O) ₂ R ⁹ , cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is,
R ⁶ is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
R ⁷ and R ⁸ are the same or different, and each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. selected from
Alternatively, R ⁷ and R ⁸ together with the linked nitrogen atom form a heterocyclyl group, and the heterocyclyl group optionally includes a halogen, an alkyl group, an oxo group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, Substituted with one or more substituents selected from a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
R ⁹ is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, is an acceptable salt;
One of these days,
Rings A, R ⁰ , R ¹ to R ⁴ , J, k, n and s are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, is an acceptable salt;
One of these days,
Rings A, R ⁰ , R ¹ to R ⁴ , R ^4a , J, k, n and s are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (III), or a pharmaceutically acceptable salt thereof, which is represented by general formula (IV) A compound or a pharmaceutically acceptable salt thereof,
One of these days,
Ring A, ring C, L, R ¹ to R ⁵ R ^4a , J, k, n, s and t are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), or a pharmaceutically acceptable salt thereof, which is represented by general formula (IIG) A compound or a pharmaceutically acceptable salt thereof,
One of these days,
Ring A, ring C, L, R ¹ to R ⁵ , J, k, n, s and t are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or its pharmaceutical Acceptable salts, in which each R ⁵ is the same or different, and each independently represents a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, - selected from NR ^c R ^d and a 3- to 12-membered heterocyclyl group, and R ^c and R ^d are the same or different, and each independently represents a hydrogen atom, a C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group. selected from heterocyclyl groups, preferably each R ⁵ is the same or different, and each independently hydrogen atom, halogen, C _1-6 alkyl group, halogenated C _1-6 alkyl group, amino group and a 3- to 6-membered heterocyclyl group, and more preferably, each R ⁵ is the same or different and each independently selected from a hydrogen atom, an amino group, and a piperazinyl group.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG) or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula A compound represented by (V) or a pharmaceutically acceptable salt thereof,
One of these days,
Ring D is a 4- to 12-membered heterocyclyl group containing at least one nitrogen atom,
R ^x is selected from a hydrogen atom, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
t is 1, 2, 3 or 4,
Ring A, ring C, L, R ¹ to R ⁵ , J, k, n and s are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG) or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof,
One of these days,
t is 1, 2, 3 or 4,
Ring A, ring C, L, R ¹ to R ⁵ , R ^d , J, k, n and s are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, and preferably, ring A is Pyridyl group or
More preferably, ring A is a pyridyl group.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which J is 0 or 1, and k is 1 or 2, preferably, J is 1, and k is 1.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein R ⁰ is a hydrogen atom, a C _1-6 alkyl group, -NR ^g R ^L and
wherein the C _1-6 alkyl group is optionally substituted with one or more -C(O)NR ⁷ R ⁸ , L, ring C, R ⁵ , R ⁷ , R ⁸ , R ^g , R ^L and t are as defined in general formula (I), and preferably R ⁰ is a hydrogen atom or
where L, ring C, R ⁵ and t are as defined in general formula (I), most preferably R ⁰ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, in which Y is a nitrogen atom, R ⁰ is a hydrogen atom, C _1-6 alkyl group and
wherein said C _1-6 alkyl group is optionally substituted with one or more -C(O)NR ⁷ R ⁸ and when Y is CR ^4a , R ⁰ is -NR ^g R ^L or
and L, ring C, R ^4a , R ⁵ , R ⁷ , R ⁸ , R ^g , R ^L and t are as defined in general formula (I).

In some preferred embodiments of the disclosure, a compound represented by the above general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein R ⁰ is Hydrogen atom, C _1-6 alkyl group, -NR ^g R ^L and
L, ring C, R ⁵ , R ^g , R ^L and t are as defined in general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, in which Y is a nitrogen atom, R ⁰ is a hydrogen atom, C _1-6 alkyl group and
and when Y is CR ^4a , R ⁰ is -NR ^g R ^L or
and L, ring C, R ^4a , R ⁵ , R ^g , R ^L and t are as defined in general formula (I).

In some preferred embodiments of the present disclosure, when Y is a nitrogen atom, R ⁰ is a hydrogen atom or a C _1-6 alkyl group, and when Y is CR ^4a , R ⁰ is -NR ^g R ^L or
and L, ring C, R ^4a , R ⁵ , R ^g , R ^L and t are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, in which R ⁰ is a hydrogen atom, a C _1-6 alkyl group, and
wherein the C _1-6 alkyl group is optionally substituted with one or more -C(O)NR ⁷ R ⁸ , L, ring C, R ⁵ , R ⁷ , R ⁸ and t are as defined in general formula (I), and preferably R ⁰ is a hydrogen atom or
where L, ring C, R ⁵ and t are as defined in general formula (I), most preferably R ⁰ is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, in which R ⁰ is a hydrogen atom, a C _1-6 alkyl group, and
L, ring C, R ⁵ and t are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, in which R ⁰ is -NR ^g R ^L or
and L, ring C, R ⁵ , R ^g , R ^L and t are as defined in general formula (I).

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ are the same or different and each independently represents a hydrogen atom or a C _1-6 alkyl group, and preferably both R ⁷ and R ⁸ are a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (III) or a pharmaceutically acceptable salt thereof, in which the above R ^g is a hydrogen atom; , R ^L is a hydrogen atom or a C _1-6 alkyl group, and preferably R ^g and R ^L are both hydrogen atoms.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which L is NR ^L or a C _1-6 alkylene group, and R ^L is a hydrogen atom or a C _1-6 alkyl group. , preferably, L is NR ^L or a C _1-6 alkylene group, and R ^L is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or its pharmaceutical an acceptable salt, wherein ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; Preferably, ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a 5- or 6-membered heteroaryl group; more preferably, ring C is selected from a tetrahydrofuranyl group, a bicyclo[2. 2.2]octyl group and pyridyl group, most preferably ring C is bicyclo[2.2.2]octyl group or pyridyl group.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or a pharmaceutical composition thereof acceptable salts, wherein L is NR ^L or a C _1-6 alkylene group, R ^L is a hydrogen atom or a C _1-6 alkyl group, and/or ring C is a 3- to 8-membered salt; These include a cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (V), general formula (VI) or its pharmaceutical Acceptable salts, in which L is a C _1-6 alkylene group.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (V) or a pharmaceutically acceptable salt thereof, in which ring C is a 5- to 10-membered heteroaryl group, Preferably, ring C is a pyridyl group.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (VI) or a pharmaceutically acceptable salt thereof, in which ring C is a 3- to 8-membered cycloalkyl group, Preferably, ring C is a bicyclo[2.2.2]octyl group.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein the above L is NR ^L , R ^L is a hydrogen atom or a C _1-6 alkyl group, preferably L is NR ^L , and R ^L is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein ring C is a 3- to 8-membered heterocyclyl group, preferably Ring C is a 3- to 6-membered heterocyclyl group, and more preferably Ring C is a tetrahydrofuranyl group.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein L is NR ^L , R ^L is a hydrogen atom or a C _1-6 alkyl group, and/or ring C is a 3- to 8-membered heterocyclyl group.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which each R ¹ is the same or different, and each independently represents a hydrogen atom, halogen, C _1-6 alkyl and a halogenated C _1-6 alkyl group, preferably each R ¹ is the same or different and each independently represents a hydrogen atom or a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which R ² is a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered R 2 is selected from membered heterocyclyl groups, preferably R ² is a C _1-6 alkyl group or a 3- to 6-membered heterocyclyl group, more preferably R ² is an isopropyl group or a tetrahydropyranyl group (e.g.
).

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group, and preferably , R ² is a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group, preferably , R ³ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which each R ⁴ is the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group. Preferably, R ⁴ is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (III), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R ^4a is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or its pharmaceutical Acceptable salts, in which each R ⁵ is the same or different, and each independently represents a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, - selected from NR ^c R ^d and a 3- to 12-membered heterocyclyl group, and R ^c and R ^d are the same or different, and each independently represents a hydrogen atom, a C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group. Preferably, each R ⁵ is homologous or different and each independently selected from a hydrogen atom, halogen, -NR ^c R ^d and a 3- to 6-membered heterocyclyl group, R ^c and R ^d are the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group; more preferably, each R ⁵ is the same or different, and each independently selected from hydrogen atoms, amino groups and piperazinyl groups.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or a pharmaceutical composition thereof Acceptable salts, in which each R ⁵ is the same or different, and each independently represents a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and 3 selected from a membered to 12-membered heterocyclyl group, preferably each R ⁵ is the same or different, and is each independently a hydrogen atom or a 3- to 6-membered heterocyclyl group, more preferably each R ⁵ are homologous or different, and each independently represents a hydrogen atom or a piperazinyl group.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (V) or a pharmaceutically acceptable salt thereof, in which each R ⁵ is homologous or different, and Each is independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group, and preferably R ⁵ is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (VI) or a pharmaceutically acceptable salt thereof, in which each R ⁵ is homologous or different, and Each is independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group, and preferably R ⁵ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II), general formula (III), or general formula (IV) or a pharmaceutically acceptable salt thereof is Among them, each R ⁵ is the same or different and each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group, and preferably R ⁵ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which n is 0, 1, 2, 3, or 4, preferably 0, 1, or 2.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which s is 0, 1, 2, 3 or 4, preferably s is 0 or 1, more preferably , s is 0.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or its pharmaceutical Acceptable salts wherein t is 0, 1, 2, 3 or 4, preferably t is 0, 1 or 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (V), general formula (VI), or a pharmaceutically acceptable salt thereof, in which t is 1, 2, 3, or 4, preferably t is 1 or 2, more preferably t is 1.

In some preferred embodiments of the present disclosure, the compound represented by the above general formula (V) or a pharmaceutically acceptable salt thereof, in which ring D is a 4-membered to It is a 12-membered heterocyclyl group, preferably Ring D is a 4- to 6-membered heterocyclyl group containing at least one nitrogen atom, and more preferably Ring D is a piperazinyl group.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (VI) or a pharmaceutically acceptable salt thereof, in which R ^d is a hydrogen atom, a C _1-6 alkyl group, and 3 R d is selected from a membered to 12-membered heterocyclyl group, and preferably R ^d is a hydrogen atom.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or a pharmaceutical composition thereof Acceptable salts, in which each R ⁵ is the same or different, and each independently represents a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, -NR ^c R ^d and a 3- to 12-membered heterocyclyl group, and R ^c and R ^d are the same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group. selected, t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or a pharmaceutical composition thereof Acceptable salts, in which each R ⁵ is the same or different, and each independently represents a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, -NR ^c R ^d and a 3- to 12-membered heterocyclyl group, and R ^c and R ^d are the same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group. selected, t is 0, 1 or 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or a pharmaceutical composition thereof Acceptable salts, in which each R ⁵ is the same or different and each independently represents a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, an amino group, and 3 selected from 6-membered to 6-membered heterocyclyl groups, and t is 0, 1 or 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) or its pharmaceutical Acceptable salts, wherein each R ⁵ is homologous or different and each independently represents -NR ^c R ^d or a 3- to 6-membered heterocyclyl group, and R ^c and R ^d are , are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group, and t is 1.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which each R ¹ is the same or different, and each independently represents a halogen, a C _1-6 alkyl group, or a halogen preferably n is 0 _, 1 or 2.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which R ¹ is a C _1-6 alkyl group, and n is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which each R ⁴ is the same or different and each independently represents a C _1-6 alkyl group, and s is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, the general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula A compound represented by (VI) or a pharmaceutically acceptable salt thereof, in which each R ⁴ is the same or different and each independently represents a C _1-6 alkyl group, and s is 0 or 1.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, comprising:
Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group,
Y is CR ^4a or a nitrogen atom,
R ^4a is a hydrogen atom,
R ⁰ is a hydrogen atom, a C _1-6 alkyl group, -NR ^g R ^L and
wherein said C _1-6 alkyl group is optionally substituted with one or more -C(O)NR ⁷ R ⁸ ,
L is a C _1-6 alkylene group or NR ^L ,
R ^g is a hydrogen atom,
R ^L is a hydrogen atom or a C _1-6 alkyl group,
Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group,
Each R ⁵ is the same or different and is independently selected from halogen, C _1-6 alkyl group, halogenated C _1-6 alkyl group, -NR ^c R ^d and 3- to 12-membered heterocyclyl group Re,
R ^c and R ^d are the same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
Each R ¹ is the same or different, and each independently selected from halogen, C _1-6 alkyl group, and halogenated C _1-6 alkyl group,
R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
Each R ⁴ is the same or different, and each independently represents a C _1-6 alkyl group,
R ⁷ and R ⁸ are the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof,
Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group,
Y is CR ^4a or a nitrogen atom,
R ^4a is a hydrogen atom,
R ⁰ is a hydrogen atom, a C _1-6 alkyl group, -NR ^g R ^L and
selected from
L is a C _1-6 alkylene group or NR ^L ,
R ^g is a hydrogen atom,
R ^L is a hydrogen atom or a C _1-6 alkyl group,
Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group,
Each R ⁵ is the same or different, and each independently represents a group consisting of a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, -NR ^c R ^d and a 3- to 12-membered heterocyclyl group. R ^c and R ^d are the same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
each R ¹ is the same or different, and each independently selected from halogen, C _1-6 alkyl group, and halogenated C _1-6 alkyl group,
R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
Each R ⁴ is the same or different, and each independently represents a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, comprising:
Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group,
Y is CR ^4a or a nitrogen atom,
R ^4a is a hydrogen atom,
R ⁰ is a hydrogen atom, a C _1-6 alkyl group, -NR ^g R ^L and
selected from
L is a C _1-6 alkylene group or NR ^L ,
R ^g is a hydrogen atom,
R ^L is a hydrogen atom or a C _1-6 alkyl group,
Ring C is a 5- to 10-membered heteroaryl group or a 3- to 8-membered heterocyclyl group,
Each R ⁵ is the same or different, and each independently selected from halogen, C _1-6 alkyl group, halogenated C _1-6 alkyl group, and 3- to 12-membered heterocyclyl group,
Each R ¹ is the same or different, and each independently selected from halogen, C _1-6 alkyl group, and halogenated C _1-6 alkyl group,
R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
Each R ⁴ is the same or different, and each independently represents a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof,
Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group,
Y is CR ^4a or a nitrogen atom,
R ^4a is a hydrogen atom,
R ⁰ is a hydrogen atom, a C _1-6 alkyl group, -NR ^g R ^L and
selected from
L is NR ^L ,
R ^g is a hydrogen atom,
R ^L is a hydrogen atom or a C _1-6 alkyl group,
Ring C is a 3- to 8-membered heterocyclyl group,
each R ⁵ is the same or different, and each independently selected from halogen, C _1-6 alkyl group, and halogenated C _1-6 alkyl group,
each R ¹ is the same or different, and each independently selected from halogen, C _1-6 alkyl group, and halogenated C _1-6 alkyl group,
R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
Each R ⁴ is the same or different, and each independently represents a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group or
and
R ⁰ is a hydrogen atom, a C _1-6 alkyl group, and
wherein said C _1-6 alkyl group is optionally substituted with one or more -C(O)NR ⁷ R ⁸ ,
L is a C _1-6 alkylene group,
Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group,
Each R ⁵ is the same or different and is independently selected from halogen, C _1-6 alkyl group, halogenated C _1-6 alkyl group, -NR ^c R ^d and 3- to 12-membered heterocyclyl group Re,
R ^c and R ^d are the same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
Each R ¹ is the same or different, and each independently selected from halogen, C _1-6 alkyl group, and halogenated C _1-6 alkyl group,
R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
Each R ⁴ is the same or different, and each independently represents a C _1-6 alkyl group,
R ⁷ and R ⁸ are the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 0 or 1, and k is 0, 1 or 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group or
and
R ⁰ is a hydrogen atom, a C _1-6 alkyl group, and
wherein said C _1-6 alkyl group is optionally substituted with one or more -C(O)NR ⁷ R ⁸ ,
L is a C _1-6 alkylene group,
Ring C is selected from a tetrahydrofuranyl group, a bicyclo[2.2.2]octyl group and a pyridyl group,
Each R ⁵ is homologous or different, and each independently represents -NR ^c R ^d or a 3- to 6-membered heterocyclyl group,
R ^c and R ^d are the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
R ¹ is a C _1-6 alkyl group,
R ² is a C _1-6 alkyl group or a 3- to 6-membered heterocyclyl group,
R ³ is a hydrogen atom,
R ⁷ and R ⁸ are the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 0 and t is 1.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
R ⁰ is a hydrogen atom, a C _1-6 alkyl group, and
selected from
L is a C _1-6 alkylene group,
Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, and a 5- to 10-membered heteroaryl group,
Each R ⁵ is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, an amino group, and a 3- to 6-membered heterocyclyl group. Re,
Each R ¹ is the same or different, and each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
Each R ⁴ is the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 1 and t is 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
R ⁰ is a hydrogen atom, a C _1-6 alkyl group, and
selected from
L is a C _1-6 alkylene group,
Ring C is a 5- to 10-membered heteroaryl group,
Each R ⁵ is the same or different, and each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
Each R ¹ is the same or different, and each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
Each R ⁴ is the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 1 and t is 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group or
and
R ⁰ is a hydrogen atom or
and
L is a C _1-6 alkylene group,
Ring C is a bicyclo[2.2.2]octyl group or a pyridyl group,
R ¹ is a C _1-6 alkyl group,
R ² is a C _1-6 alkyl group or a 3- to 6-membered heterocyclyl group,
R ³ is a hydrogen atom,
Each R ⁵ is homologous or different, and each independently represents -NR ^c R ^d or a 3- to 6-membered heterocyclyl group,
R ^c and R ^d are the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
t is 1,
J is 1, and k is 1,
n is 0, 1 or 2, and s is 0.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group or
and
R ⁰ is a hydrogen atom or a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally substituted with one or more -C(O)NR ⁷ R ⁸ ,
R ¹ is a C _1-6 alkyl group,
R ² is a C _1-6 alkyl group or a 3- to 6-membered heterocyclyl group,
R ³ is a hydrogen atom,
R ⁷ and R ⁸ are the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2, and s is 0.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
R ⁰ is a hydrogen atom,
R ¹ is a C _1-6 alkyl group,
R ² is a C _1-6 alkyl group,
R ³ is a hydrogen atom,
J is 1, and k is 1,
n is 0, 1 or 2, and s is 0.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (IIG) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
L is a C _1-6 alkylene group,
Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a 5- or 6-membered heteroaryl group,
Each R ⁵ is the same or different, and each independently selected from halogen, C _1-6 alkyl group, halogenated C _1-6 alkyl group, amino group, and 3- to 6-membered heterocyclyl group,
each R ¹ is the same or different, and each independently selected from halogen, C _1-6 alkyl group, and halogenated C _1-6 alkyl group,
R ² is selected from halogen, C _1-6 alkyl group, halogenated C _1-6 alkyl group, and 3- to 12-membered heterocyclyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 0, and k is 0, 1 or 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (IIG) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
L is a C _1-6 alkylene group,
Ring C is selected from a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, and a 5- to 10-membered heteroaryl group,
Each R ⁵ is the same or different, and each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, an amino group, and a 3- to 6-membered heterocyclyl group. Re,
Each R ¹ is the same or different, and each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
Each R ⁴ is the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 1 and t is 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (IIG) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
L is a C _1-6 alkylene group,
Ring C is a 5- to 10-membered heteroaryl group,
Each R ⁵ is the same or different, and each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
Each R ¹ is the same or different, and each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
Each R ⁴ is the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 1 and t is 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (V) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
L is a C _1-6 alkylene group,
Ring C is a pyridyl group,
Ring D is a 4- to 6-membered heterocyclyl group containing at least one nitrogen atom,
R ^x is selected from a hydrogen atom, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
R ¹ is a C _1-6 alkyl group,
R ² is a C _1-6 alkyl group or a 3- to 6-membered heterocyclyl group,
R ³ is a hydrogen atom,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 0 and t is 1.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (V) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
L is a C _1-6 alkylene group,
Ring C is a pyridyl group,
Ring D is a 4- to 6-membered heterocyclyl group containing at least one nitrogen atom,
R ^x is selected from a hydrogen atom, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
R ⁵ is a hydrogen atom,
Each R ¹ is the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
R ² is a C _1-6 alkyl group or a 3- to 6-membered heterocyclyl group,
R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 1 and t is 2.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (VI) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
L is a C _1-6 alkylene group,
Ring C is a 3- to 8-membered cycloalkyl group,
R ¹ is a C _1-6 alkyl group,
R ² is a C _1-6 alkyl group or a 3- to 6-membered heterocyclyl group,
R ³ is a hydrogen atom, J is 1, and k is 1,
n is 0, 1 or 2,
s is 0 and t is 1.

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (VI) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group,
L is a C _1-6 alkylene group,
Ring C is a 3- to 8-membered cycloalkyl group,
R ⁵ is a hydrogen atom,
Each R ¹ is the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
R ² is a C _1-6 alkyl group or a 3- to 6-membered heterocyclyl group,
R ³ is a hydrogen atom,
R ⁴ is a hydrogen atom,
J is 1, and k is 1,
n is 0, 1 or 2,
s is 1 and t is 2.

Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof:
One of these days,
Rings A, R ¹ to R ⁴ , J, k, n and s are as defined in the compound of general formula (II).

Another aspect of the present disclosure relates to a compound represented by general formula (IVA), or a pharmaceutically acceptable salt thereof:
One of these days,
Rings A, R ¹ to R ⁴ , R ^4a , R ^L , J, k, n and s are as defined in the compound of general formula (IV).

Another aspect of the present disclosure relates to a compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof:
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
Rings A, R ¹ to R ⁴ , J, k, n and s are as defined in the compound of general formula (II).

Another aspect of the present disclosure relates to a compound represented by general formula (VA), or a pharmaceutically acceptable salt thereof:
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
Ring D is a 4- to 12-membered heterocyclyl group containing at least one nitrogen atom,
t is 1, 2, 3 or 4,
Ring A, ring C, L, R ¹ to R ⁵ , J, k, n and s are as defined in general formula (V).

Another aspect of the present disclosure relates to a compound represented by general formula (VIA), or a pharmaceutically acceptable salt thereof:
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
t is 1, 2, 3 or 4,
Ring A, ring C, L, R ¹ to R ⁵ , R ^d , J, k, n and s are as defined in general formula (VI).

In some preferred embodiments of the present disclosure, a compound represented by the above general formula (IIA) or a pharmaceutically acceptable salt thereof,
Ring A is a pyridyl group or
and
R ¹ is a C _1-6 alkyl group,
R ² is a C _1-6 alkyl group,
R ³ is a hydrogen atom,
J is 1, and k is 1,
n is 0, 1 or 2, and s is 0.

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
A compound of general formula (IIA) or a pharmaceutically acceptable salt thereof is subjected to a nucleophilic substitution reaction with R ⁰ -X to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof. ,
One of these days,
X is a leaving group, preferably halogen, more preferably bromine or iodine,
R ⁰ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a haloalkyl group, a hydroxyalkyl group, and
Among them, the alkyl group is optionally an alkoxy group, a haloalkoxy group, a cyano group, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , a cycloalkyl group, a heterocyclyl group, an aryl group. and a heteroaryl group, preferably R ⁰ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a haloalkyl group, a hydroxyalkyl group, and
selected from
L is a chemical bond or an alkylene group, where the alkylene group optionally includes a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group. , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group,
Ring A, ring C, R ¹ to R ⁵ , n, s, t, J and k are as defined in the compound of general formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIG) or a pharmaceutically acceptable salt thereof, the method comprising:
A compound of general formula (IIA) or a pharmaceutically acceptable salt thereof is subjected to a nucleophilic substitution reaction with a compound of general formula (XI) to obtain a compound of general formula (IIG) or a pharmaceutically acceptable salt thereof. , including;
One of these days,
X is a leaving group, preferably halogen, more preferably bromine or iodine,
L is a chemical bond or an alkylene group, where the alkylene group optionally includes a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group. , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group,
Ring A, ring C, R ¹ to R ⁵ , n, s, t, J and k are as defined in the compound of general formula (IIG).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof, the method comprising:
removing the protecting group R ^w from the compound of general formula (IIB) or a pharmaceutically acceptable salt thereof to obtain a compound of general formula (IIA) or a pharmaceutically acceptable salt thereof,
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
Ring A, R ¹ to R ⁴ , n, s, J and k are as defined in general formula (IIA).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:
A compound of general formula (IVA) or a pharmaceutically acceptable salt thereof is subjected to a reductive amination reaction with a compound of general formula (IVB) to obtain a compound of general formula (IV) or a pharmaceutically acceptable salt thereof. including,
One of these days,
L is NR ^L ,
R ^L is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and preferably R ^L is a hydrogen atom or C _1-6 alkyl group,
Ring A, ring C, R ¹ to R ⁵ , R ^4a , n, s, t, J and k are as defined in general formula (IV).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:
The protecting group R ^w is removed from the compound of general formula (VA) or a pharmaceutically acceptable salt thereof, optionally further reacted with an alkylating agent R ^x -W, and the compound of general formula (V) or its pharmaceutically acceptable salt is removed. obtaining a pharmaceutically acceptable salt;
One of these days,
W is a leaving group, preferably halogen;
R ^x is selected from a hydrogen atom, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
Ring D is a 4- to 12-membered heterocyclyl group containing at least one nitrogen atom,
t is 1, 2, 3 or 4,
Ring A, ring C, L, R ¹ to R ⁵ , J, k, n and s are as defined in general formula (V).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:
removing the protecting group R ^w from the compound of general formula (VIA) or a pharmaceutically acceptable salt thereof to obtain a compound of general formula (VI) or a pharmaceutically acceptable salt thereof;
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
t is 1, 2, 3 or 4,
Ring A, ring C, L, R ¹ to R ⁵ , R ^d , J, k, n and s are as defined in general formula (VI).

Another aspect of the present disclosure is general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula ( VI) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents or excipients.

The present disclosure further provides general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting TLR7 and/or TLR8 and/or TLR9.

The present disclosure further provides general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) and Table A Use of a compound shown in , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting TLR7, TLR8 or TLR9, preferably a medicament for inhibiting TLR7 or in the preparation of a medicament for inhibiting TLR7 and TLR8; or in the preparation of a medicament for inhibiting TLR7 and TLR9.

The present disclosure further provides general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) and Table A or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting TLR7, TLR8 and TLR9.

The present disclosure further provides general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) and Table A or a pharmaceutical composition containing the same, in the preparation of a medicament for treating and/or preventing inflammatory or autoimmune diseases; Preferably, the sexual or autoimmune disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjögren's syndrome.

The present disclosure further provides a method of inhibiting TLR7 and/or TLR8 and/or TLR9, comprising administering to a patient in need thereof a therapeutically effective amount of general formula (I), general formula (II), general formula (IIG), Administration of a compound represented by general formula (III), general formula (IV), general formula (V), general formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. Relating to a method comprising:

The present disclosure further provides a method of inhibiting TLR7, TLR8, TLR9, preferably a method of inhibiting TLR7, preferably a method of inhibiting TLR7 and TLR8, preferably a method of inhibiting TLR7 and TLR9, comprising: A therapeutically effective amount of general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further provides a method of inhibiting TLR7, TLR8 and TLR9, comprising administering a therapeutically effective amount of general formula (I), general formula (II), general formula (IIG), general formula (III) to a patient in need thereof. ), general formula (IV), general formula (V), general formula (VI) and a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Regarding the method.

The present disclosure further provides a method of treating and/or preventing an inflammatory or autoimmune disease, comprising administering a therapeutically effective amount of a compound of general formula (I), general formula (II), general formula (IIG) to a patient in need thereof. , general formula (III), general formula (IV), general formula (V), general formula (VI) and the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. wherein said inflammatory or autoimmune disease is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjögren's syndrome.

The present disclosure further provides general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula ( VI) and the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further provides general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV) used to inhibit TLR7 and/or TLR8 and/or TLR9. ), general formula (V), general formula (VI) and the compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The present disclosure further provides for use in inhibiting TLR7, TLR8 or TLR9, preferably for inhibiting TLR7, or for inhibiting TLR7 and TLR8, or for inhibiting TLR7 and TLR9. General formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), general formula (VI) used for and shown in Table A The present invention relates to a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The present disclosure further provides general formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V), the compound shown in general formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The present disclosure further provides general formula (I), general formula (II), general formula (IIG), general formula (III), general formula ( IV), a compound shown in general formula (V), general formula (VI) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, among which the above-mentioned inflammatory or autoimmune diseases is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjögren's syndrome.

In view of the activity as a selective inhibitor of TLR7, TLR8 or TLR9, formula (I), general formula (II), general formula (IIG), general formula (III), general formula (IV), general formula (V) , general formula (VI) and Table A can be used to treat TLR7, TLR8 or TLR9 family receptor related diseases, respectively, which diseases include inflammatory diseases (e.g. Crohn's disease, ulcerative colon inflammation, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease), autoimmune diseases (e.g., Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, psoriasis), autoinflammation Sexual diseases (including Cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF), adult-onset Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis) ), metabolic diseases (including type 2 diabetes, atherosclerosis, myocardial infarction), destructive bone disorders (e.g., bone resorptive diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders), proliferative disorders (e.g. acute myeloid leukemia, chronic skeletal leukemia), angiogenic disorders (e.g. ocular neovascularization and angiogenic disorders in childhood hemangiomas), infectious diseases (e.g. sepsis, septic shock and shigellosis), Neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, cerebral ischemia due to traumatic injury or neurodegenerative diseases), tumor diseases (e.g. metastatic melanoma, Kaposi's sarcoma, multiple myeloma) and viral diseases (e.g. including, but not limited to, HIV infection and CMV retinitis, AIDS).

More specifically, specific medical conditions or diseases that can be treated using the compounds of the present disclosure include pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, joint Rheumatism, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic Active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, pulmonary tuberculosis, atherosclerosis, muscle Cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic β-cell disease, and a disease characterized by massive neutrophil infiltration. , rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary nodular disease, bone resorption disease, allograft rejection, fever and muscle pain due to infection, Cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi Sarcoma, multiple myeloma, sepsis, septic shock and shigellosis, Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative diseases due to traumatic injury, angiogenic disorders including ocular neovascularization and childhood hemangiomas, acute hepatitis Infectious diseases (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, viral diseases including AIDS, ARC or malignant tumors and herpes, stroke, myocardial ischemia, stroke and heart attack. Local ischemia, organ hypoxia, vascular hyperplasia, cardiac/kidney reperfusion injury, thrombus formation, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, prostaglandin endoperoxidase including, but not limited to, synthase-2 related diseases, and pemphigus vulgaris. In a preferred method of treatment, the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris. In an alternatively preferred treatment method, the condition is ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury due to stroke and myocardial ischemia-reperfusion injury due to myocardial infarction. In another preferred treatment, the condition is multiple myeloma.

The active compounds can be made in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be prepared using one or more pharmaceutically acceptable vectors in a conventional manner. Accordingly, the active compounds of the present disclosure can be prepared in dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure can be formulated into sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, topical tablets or syrups. may be done.

As a general guide, it is preferred that the active compound is in unit dose form or in a form that can be self-administered by the patient as a single agent. The unit dose representation of a compound or composition of the present disclosure may be a tablet, capsule, cachet, bottled solution, drug powder, granule, topical tablet, suppository, reconstituted powder, or liquid formulation. Suitable unit doses may be from 0.1 mg to 1000 mg.

Pharmaceutical compositions according to the present disclosure may contain, in addition to the active compound, one or more additives, such as fillers (diluents), binders, wetting agents, disintegrants or excipients. Selected from ingredients such as agents. The compositions may contain from 0.1% to 99% by weight of active compound, depending on the method of administration.

Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients for mixing with which are suitable for the preparation of tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that provide sustained release effects over extended periods of time by masking the taste of the drug and slowing its disintegration and absorption in the gastrointestinal tract. .

Oral formulations may be presented in soft gelatin capsules in which the active ingredient is admixed with an inert solid diluent, or the active ingredient therein and a water-soluble vector or an oily solvent.

Aqueous suspensions contain the active materials and excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspensions may contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oily suspensions may be prepared by suspending the active ingredient in vegetable or mineral oil. The oily suspensions may also contain a thickening agent. Sweeteners and flavoring agents may be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants.

Pharmaceutical compositions according to the present disclosure may be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids and the emulsion may contain sweeteners, flavoring agents, preservatives and antioxidants. Such formulations may also contain emollients, preservatives, colorants and antioxidants.

Pharmaceutical compositions according to the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable solvents or solvents that may be used include water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injectable solution or microemulsion is injected into the patient's bloodstream by local injection in large quantities. can do. Alternatively, it is preferred to administer solutions and microemulsions in a manner that allows constant cyclic concentrations of the compounds of the present disclosure to be maintained. To maintain such constant concentrations, a continuous intravenous administration device can be used. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous injection pump.

Pharmaceutical compositions according to the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any compounding fixed oil can be used. Injections can also be prepared from fatty acids.

Compounds according to the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum and thus dissolves and releases the drug in the rectum. I can do it.

Compounds of the present disclosure can be administered by adding water to prepare aqueous suspensions, dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing agent, wetting agent, suspending agent, and one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug depends on many factors, including the activity of the specific compound used, the age of the patient, the weight of the patient, and the patient's physical condition. including, but not limited to, patient behavior, patient diet, time of administration, mode of administration, rate of excretion, composition of the drug, severity of the disease, etc., as well as the optimal treatment method, e.g., mode of treatment, compound The daily dosage or type of pharmaceutically acceptable salts, etc. can be verified according to conventional treatment regimens.

DESCRIPTION OF TERMS Unless otherwise specified to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl group" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7) groups. , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms (i.e. C _{1 -20} alkyl group). The above alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C _1-12 alkyl group), and an alkyl group having 1 to 6 carbon atoms (i.e., C _1-6 alkyl group). group) is more preferable. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1 -dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2 -Methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5- Methylhexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n- Octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group , 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, It includes 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched chain isomers thereof. Most preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. -butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3 -Methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethyl Includes butyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. Alkyl groups may be substituted or unsubstituted, and if substituted, they may be substituted at any available point of attachment, and the substituents include D atoms, halogen, alkoxy groups, haloalkyl groups, halo One or more selected from alkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. It is preferable.

The term "alkylene group" refers to a divalent alkyl group, in which the alkyl group is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms (ie, a C _1-20 alkylene group). The above alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C _1-12 alkylene group), and an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 alkylene group). group) is more preferable. Non-limiting examples of alkylene groups include methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH ₂ CH ₂ )-, 1,1 -Propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4 -butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. Alkylene groups may be substituted or unsubstituted, and if substituted, they may be substituted at any available linking site, and the substituents include alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups. , cycloalkyloxy group, heterocyclyloxy group, alkylthio group, alkylamino group, halogen, mercapto group, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkoxy group, hetero Preferably, it is one or more selected from a cycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, and an oxo group.

The term "heteroalkyl group" means that one or more (preferably 1, 2, 3, 4 or 5) -CH ₂ - in an alkyl group is a heteroatom selected from N, O and S. , in which the alkyl group is as defined above. Heteroalkyl groups may be substituted or unsubstituted, and if substituted, they may be substituted at any available point of attachment, and the substituents include deuterium atoms, halogens, alkoxy groups, haloalkyl groups. , haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group. It is preferable that

The term "alkenyl group" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, where alkyl group is as defined above, and from 2 to 12 (e.g., 2, (ie, a C _2-12 alkenyl group). The above alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkenyl group). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents include alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxy Preferably, it is one or more selected from an alkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

The term "alkynyl group" refers to an alkyl group in which the molecule contains at least one carbon-carbon triple bond, in which the alkyl group is as defined above, and from 2 to 12 (e.g., 2, (ie, a C _2-12 alkynyl group). The above alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C _2-6 alkynyl group). Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents include alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxy Preferably, it is one or more selected from an alkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

The term "alkoxy group" refers to -O-(alkyl group), in which alkyl group is defined as above. Non-limiting examples include methoxy, ethoxy, propoxy and butoxy groups. The alkoxy group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents include deuterium atoms, halogens, alkoxy groups, haloalkyl groups, One or more selected from haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group. It is preferable that there be.

The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having from 3 to 20 cycloalkyl rings (e.g., 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms (i.e., a 3- to 20-membered cycloalkyl group), preferably 3 to 12 carbon atoms (i.e., a 3- to 12-membered cycloalkyl group), and more preferably 3 to 8 carbon atoms. carbon atoms (ie, a 3- to 8-membered cycloalkyl group), and most preferably 3 to 6 carbon atoms (ie, a 3- to 6-membered cycloalkyl group). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and Polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.

The term "spirocycloalkyl group" refers to a 5- to 20-membered polycyclic group in which the rings share one carbon atom (referred to as the spiro atom) and contains one or more double bonds. But that's fine. It is preferably 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 or 10 members). Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into monospirocycloalkyl groups or polyspirocycloalkyl groups (e.g. bisspirocycloalkyl groups), preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. It is a spirocycloalkyl group. More preferably, 3/5 members, 3/6 members, 4/4 members, 4/5 members, 4/6 members, 5/5 members, 5/6 members, 6/4 members a 6-membered/5-membered or 6-membered/6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups are:
including.

The term "fused cycloalkyl group" refers to a 5- to 20-membered, all-carbon polycyclic group in which the rings share a pair of adjacent carbon atoms, in which one or more rings share one pair of carbon atoms. Or it may contain multiple double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 or 10 members). Depending on the number of constituent rings, it can be divided into polycyclic fused cycloalkyl groups such as bicyclic, tricyclic, and tetracyclic, and preferably bicyclic or tricyclic fused cycloalkyl groups. , more preferably 3/4 members, 3/5 members, 3/6 members, 4/4 members, 4/5 members, 4/6 members, 5/3 members, 5 members/4 members members, 5 members/5 members, 5 members/6 members, 5 members/7 members, 6 members/3 members, 6 members/4 members, 6 members/5 members, 6 members/6 members, 6 members/7 members, It is a 7-membered/5-membered or 7-membered/6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups are:
including.

The term "bridged cycloalkyl group" refers to a 5- to 20-membered all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected; may contain a double bond. It is preferably 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 or 10 members). Depending on the number of constituent rings, it can be divided into polycyclic bridged cycloalkyl groups such as bicyclic, tricyclic, and tetracyclic, and preferably bicyclic, tricyclic, and tetracyclic bridged cycloalkyl groups. It is an alkyl group, more preferably a bicyclic or tricyclic bridged cycloalkyl group. Non-limiting examples of bridged cycloalkyl groups are:
including.

The above-mentioned cycloalkyl ring includes those in which the above-mentioned cycloalkyl group (including a monocyclic ring, a spiro ring, a fused ring, and a bridged ring) is fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, and among these, the parent structure The ring connected to is a cycloalkyl group, non-limiting examples of which are:
including,
is preferred.

Cycloalkyl groups may be substituted or unsubstituted, and if substituted, they may be substituted at any available point of attachment, and the substituents include halogen, alkyl groups, alkoxy groups, haloalkyl groups, One or more selected from haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group. It is preferable that there be.

The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having from 3 to 20 ring atoms, in which one or more ring atoms -O-O-, -O-S It does not contain a ring moiety of - or -SS-, and the remaining ring atoms are carbon. Preferably, it has 3 to 12 ring atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12), of which 1 -4 (e.g., 1, 2, 3, and 4) are heteroatoms (i.e., 3- to 12-membered heterocyclyl groups) (e.g., 4- to 12-membered heteroatoms containing at least one nitrogen atom) heterocyclyl group), more preferably 3 to 8 (e.g. 3, 4, 5, 6, 7 and 8) ring atoms, of which 1 to 3 (e.g. 1 , 2 and 3) are heteroatoms (i.e., 3- to 8-membered heterocyclyl groups), more preferably have 3 to 6 ring atoms, of which 1 to 3 are heteroatoms. (i.e., a 3- to 6-membered heterocyclyl group) (e.g., a 4- to 6-membered heterocyclyl group containing at least one nitrogen atom), most preferably having 5 or 6 ring atoms, of which 1 3 to 3 are heteroatoms (ie, a 5- or 6-membered heterocyclyl group). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. . Polycyclic heterocyclyl groups include spiroheterocyclyl groups, fused heterocyclyl groups and bridged heterocyclyl groups.

The term "spiroheterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (referred to as a spiro atom), in which one or more ring atoms A heteroatom selected from nitrogen, oxygen and sulfur, the sulfur optionally being substituted with an oxo group (ie forming a sulfoxide or sulfone) and the remaining ring atoms being carbon. It may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 or 10 members). Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl groups are divided into monospiroheterocyclyl groups or polyspiroheterocyclyl groups (e.g. bisspiroheterocyclyl groups), preferably monospiroheterocyclyl groups and bisspiroheterocyclyl groups. . More preferably, 3/5 members, 3/6 members, 4/4 members, 4/5 members, 4/6 members, 5/5 members, 5/6 members, or 6/6 members. It is a member monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are:
including.

The term "fused heterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which the rings share a pair of adjacent atoms, and one or more rings contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally substituted with an oxo group (i.e., sulfoxide or sulfone). ), the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 or 10 members). Depending on the number of constituent rings, it can be divided into polycyclic fused heterocyclyl groups such as bicyclic, tricyclic, and tetracyclic, preferably bicyclic or tricyclic fused heterocyclyl groups, and more Preferably 3/4 members, 3/5 members, 3/6 members, 4/4 members, 4/5 members, 4/6 members, 5/3 members, 5/4 members, 5/5 members, 5/6 members, 6/3 members, 6/4 members, 6/5 members, 6/6 members, 6/7 members, 7/5 members or 7 members /6-membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are:
including.

The term "bridged heterocyclyl group" refers to a 5- to 14-membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, and which has one or more double bonds. wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally substituted with an oxo group (i.e. forming a sulfoxide or sulfone). ), the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members (eg, 7, 8, 9 or 10 members). Depending on the number of constituent rings, it can be divided into polycyclic bridged heterocyclyl groups such as bicyclic, tricyclic, and tetracyclic, and preferably bicyclic, tricyclic, and tetracyclic bridged heterocyclyl groups. and more preferably a bicyclic or tricyclic bridged heterocyclyl group. Non-limiting examples of bridged heterocyclyl groups are:
including.

The above-mentioned heterocyclyl ring includes those in which the above-mentioned heterocyclyl group (including monocycle, spiroheterocycle, fused heterocycle, and bridged heterocycle) is fused to an aryl group, heteroaryl group, or cycloalkyl ring; The linked ring is a heterocyclyl group, non-limiting examples of which are:
Including.

A heterocyclyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available point of attachment, and the substituents include halogen, alkyl, alkoxy, haloalkyl, halo One or more selected from alkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. It is preferable.

The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group with a conjugated pi-electron system. It is preferably 6- to 10-membered, such as phenyl and naphthyl groups. The above aryl ring includes the above aryl ring fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, in which the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include: ,
including.

Aryl groups may be substituted or unsubstituted, and if substituted, they may be substituted at any available point of attachment, and the substituents include halogen, alkyl groups, alkoxy groups, haloalkyl groups, halo One or more selected from alkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. It is preferable.

The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, of which , the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5- to 10-membered (for example, 5-, 6-, 7-, 8-, 9-, or 10-membered) heteroaryl group, more preferably a 5- or 6-membered heteroaryl group, for example, Examples include furanyl group, thienyl group, pyridyl group, pyrrolyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, imidazolyl group, pyrazolyl group, triazolyl group, and tetrazolyl group. The above-mentioned heteroaryl ring includes the above-mentioned heteroaryl group fused to an aryl group, heterocyclyl group, or cycloalkyl ring, in which the ring connected to the parent structure is a heteroaryl ring, and the non-limiting An example is
including.

Heteroaryl groups may be substituted or unsubstituted, and if substituted, they may be substituted at any available point of attachment, and the substituents include halogen, alkyl groups, alkoxy groups, haloalkyl groups, One or more selected from haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group. It is preferable that there be.

The above cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are residues derived by removing one hydrogen atom from a parent ring atom, or residues derived from the same ring atom or two different ring atoms of the parent parent. It includes residues derived by removing a hydrogen atom, ie, "cycloalkylene group," "heterocyclylene group," "arylene group," and "heteroarylene group."

The term "amino protecting group" refers to an easily eliminated group that is introduced into an amino group so that the amino group is not changed when other parts of the molecule are reacted. Non-limiting examples include (trimethylsilicon)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, benzyloxycarbonyl (Cbz), allyl and p-methoxybenzyl. Including groups, etc. These groups can optionally be substituted with 1 to 3 substituents selected from halogen, alkoxy group or nitro group.

The term "hydroxy protecting group" refers to a susceptible group that is introduced into a hydroxy group and generally performs a reaction on another functional group of the compound to block or protect the hydroxy group. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilane (TBS), tert-butyldiphenylsilyl, methyl, tert- Includes butyl, allyl group, benzyl group, methoxymethyl group (MOM), ethoxyethyl group, 2-tetrahydropyranyl group (THP), formyl group, acetyl group, benzoyl group, p-nitrobenzoyl group, etc.

The term "cycloalkyloxy group" refers to cycloalkyl-O-, in which the cycloalkyl group is as defined above.

The term "heterocyclyloxy group" refers to heterocyclyl-O-, in which the heterocyclyl group is as defined above.

The term "aryloxy group" refers to aryl-O-, in which the aryl group is as defined above.

The term "heteroaryloxy group" refers to heteroaryl-O-, in which the heteroaryl group is as defined above.

The term "alkylthio group" refers to alkyl-S-, in which the alkyl group is as defined above.

The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, in which the alkoxy group is as defined above.

The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy group" refers to -OH.

The term "mercapto group" refers to -SH.

The term "amino group" refers to _-NH2 .

The term "cyano group" refers to -CN.

The term "nitro group" refers to _-NO2 .

The term "oxo group" or "oxo" refers to "=O".

The term "carbonyl group" refers to C=O.

The term "aldehyde group" refers to -C(O)H.

The term "carboxy group" refers to -C(O)OH.

The term "carboxylic acid ester" means -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O- of which the alkyl group and cycloalkyl group are as defined above.

In the chemical structure of the compounds described in this disclosure, “
” indicates that the configuration is unspecified, i.e., if a chiral isomer exists in the chemical structure, “
” is the combination “
” or “
” or “
"as well as"
” may be included at the same time.

The compounds and intermediates of this disclosure may exist in different tautomeric forms, and all such forms are included within the scope of this disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible due to a low energy barrier. Examples include keto-enol, imine-enamine, lactam-lactim isomerization. An example of a lactam-lactim equilibrium is between A and B as shown below:
.

All tautomeric forms are within the scope of this disclosure. Nomenclature of compounds does not exclude any tautomeric forms.

The disclosure further provides isotopes as described herein, but in which one or more atoms are substituted with an atom having an atomic weight or mass number that differs from that normally found in nature. including some of the compounds of the present disclosure. Examples of isotopes that can be bound to compounds of the present disclosure include hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine and chlorine isotopes, e.g. ^{, 2} H, ³ H, ¹¹ C, ¹³ respectively. C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I, and ³⁶ Cl. Such compounds may be used, for example, as analytical tools or probes in bioassays, or as imaging tracers for in vivo diagnosis of diseases, or in pharmacodynamic, pharmacokinetic or receptor May be used as a research tracer.

"Optionally" or "optional" means that the subsequently described event or situation may or may not occur; Including cases where this does not occur. For example, "a C _1-6 alkyl group optionally substituted with a halogen or cyano group" means that the halogen or cyano group may be present, but may not be present. This description includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

"Substituted" means that one or more hydrogen atoms, preferably 1 to 6 hydrogen atoms, more preferably 1 to 3 hydrogen atoms, in a group are independently substituted with a corresponding number of substituents. Refers to being done. A person skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) without much effort. For example, amino or hydroxy groups with free hydrogen can become unstable if attached to a carbon atom with an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components and a physiologically/pharmaceutically acceptable salt or prodrug thereof; and other components such as a vector and excipients that are acceptable to the public. Pharmaceutical compositions are intended to facilitate administration to living organisms, contribute to the absorption of active ingredients, and exhibit biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound according to the present disclosure, and may be selected from inorganic or organic salts. Such salts are safe and effective when used within the mammalian body, and have desirable biological activity. Salts may be prepared during the final isolation and purification process of the compound or alone by reacting a suitable group with a suitable base or acid. Generally, bases for forming pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. Generally, acids for forming pharmaceutically acceptable salts include inorganic acids and organic acids.

For a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic dose of the drug or agent sufficient to produce the desired effect. Effective amounts are human-determinable and depend on the age and general condition of the subject, as well as on the specific active substance, and a suitable effective amount for an individual can be determined by one of ordinary skill in the art by routine trials. can be done.

As used herein, the term "solvate" refers to the physical association of a compound according to the present disclosure with one or more, preferably one to three, organic or inorganic solvent molecules. refers to Such physical bonds include hydrogen bonds. In some cases, solvates will be separated, for example if one or more, preferably one to three, solvent molecules are incorporated into the crystal lattice of the crystalline solid. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are known in the art.

As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and/or dosage forms have no undue toxicity, irritation, or allergy within the range of reasonable medical judgment. Means that it is free of reactions or other problems or complications, is applied in contact with patient tissue, has a reasonable benefit/loss ratio, and is effective for the desired application.

As used herein, the singular forms "a," "a," and "an" include plural references and vice versa, unless the context clearly dictates otherwise.

The term "about" when used for a parameter such as pH, concentration, temperature, etc. indicates that this parameter may be varied by ±10%, and in some cases more preferably by ±5%. As will be understood by those skilled in the art, where a parameter is not critical, numbers are generally given for illustrative purposes only and not as a limitation.

Method for Synthesizing Compounds According to the Present Disclosure In order to achieve the objectives of the present disclosure, the present disclosure adopts the following technical schemes.

Technical proposal 1
A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof according to the present disclosure, the method comprising the following steps:
removing the protecting group R ^w from the compound of general formula (IIB) or a pharmaceutically acceptable salt thereof to obtain a compound of general formula (IIA) or a pharmaceutically acceptable salt thereof; ) or a pharmaceutically acceptable salt thereof with R ⁰ -X under basic conditions to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof. including,
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
X is a leaving group, preferably halogen, more preferably bromine or iodine,
^R0 is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a haloalkyl group, a hydroxyalkyl group, and
Among them, the alkyl group is optionally an alkoxy group, a haloalkoxy group, a cyano group, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , a cycloalkyl group, a heterocyclyl group, an aryl group. and a heteroaryl group, preferably R ⁰ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a haloalkyl group, a hydroxyalkyl group, and
selected from
L is a chemical bond or an alkylene group, where the alkylene group optionally includes a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group. , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group,
Ring A, ring C, R ¹ to R ⁵ , n, s, t, J and k are as defined in the compound of general formula (II).

Technical plan 2
A method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof according to the present disclosure, the method comprising the following steps:
The compound of general formula (IVA) or its pharmaceutically acceptable salt is subjected to a reductive amination reaction with the compound of general formula (IVB) in the presence of a reducing agent, and the compound of general formula (IV) or its pharmaceutically acceptable salt is reacted with the compound of general formula (IVB) in the presence of a reducing agent. obtaining acceptable salt;
One of these days,
L is NR ^L ,
R ^L is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and preferably R ^L is a hydrogen atom or C _1-6 alkyl group,
Ring A, ring C, R ¹ to R ⁵ , R ^4a , n, s, t, J and k are as defined in general formula (IV).

Technical plan 3
A method for preparing a compound represented by general formula (IIG) or a pharmaceutically acceptable salt thereof according to the present disclosure, the method comprising the following steps:
The compound of general formula (IIA) or its pharmaceutically acceptable salt is subjected to a nucleophilic substitution reaction with the compound of general formula (XI) under basic conditions, and the compound of general formula (IIG) or its pharmaceutically acceptable salt is reacted with the compound of general formula (XI) under basic conditions. obtaining salt;
One of these days,
X is a leaving group, preferably halogen, more preferably bromine or iodine,
L is a chemical bond or an alkylene group, where the alkylene group optionally includes a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group. , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group,
Ring A, ring C, R ¹ to R ⁵ , n, s, t, J and k are as defined in the compound of general formula (IIG).

Technical plan 4
A method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof according to the present disclosure, the method comprising the following steps:
removing the protecting group R ^w from the compound of general formula (VA) or a pharmaceutically acceptable salt thereof under acidic conditions and optionally further reacting with an alkylating agent R ^x -W under basic conditions; Obtaining a compound of general formula (V) or a pharmaceutically acceptable salt thereof,
One of these days,
W is a leaving group, preferably halogen;
R ^x is selected from a hydrogen atom, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
Ring D is a 4- to 12-membered heterocyclyl group containing at least one nitrogen atom,
t is 1, 2, 3 or 4,
Ring A, ring C, L, R ¹ to R ⁵ , J, k, n and s are as defined in general formula (V).

Technical plan 5
A method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof according to the present disclosure, the method comprising the following steps:
removing the protecting group R ^w from the compound of general formula (VIA) or its pharmaceutically acceptable salt under acidic conditions to obtain the compound of general formula (VI) or its pharmaceutically acceptable salt; including,
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
t is 1, 2, 3 or 4,
Ring A, ring C, L, R ¹ to R ⁵ , R ^d , J, k, n and s are as defined in general formula (VI).

Technical plan 6
A method for preparing a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof according to the present disclosure, the method comprising the following steps:
removing the protecting group R ^w from the compound of general formula (IIB) or a pharmaceutically acceptable salt thereof under acidic conditions to obtain the compound of general formula (IIA) or a pharmaceutically acceptable salt thereof; including,
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
Ring A, R ¹ to R ⁴ , n, s, J and k are as defined in general formula (IIA).

Technical plan 7
A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof according to the present disclosure, the method comprising the following steps:
A compound of general formula (IIA) or a pharmaceutically acceptable salt thereof is subjected to a nucleophilic substitution reaction with R ⁰ -X under basic conditions to form a compound of general formula (II) or a pharmaceutically acceptable salt thereof. including obtaining;
One of these days,
X is a leaving group, preferably halogen, more preferably bromine or iodine,
^R0 is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a haloalkyl group, a hydroxyalkyl group, and
Among them, the alkyl group is optionally an alkoxy group, a haloalkoxy group, a cyano group, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , a cycloalkyl group, a heterocyclyl group, an aryl group. and a heteroaryl group, preferably R ⁰ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a haloalkyl group, a hydroxyalkyl group, and
selected from
L is a chemical bond or an alkylene group, where the alkylene group optionally includes a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group. , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group,
Ring A, ring C, R ¹ to R ⁵ , n, s, t, J and k are as defined in the compound of general formula (II).

Technical plan 8
A method for preparing a compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof according to the present disclosure, the method comprising the following steps:
A compound of general formula (IIa) or a pharmaceutically acceptable salt thereof is combined with a compound of general formula (IIb) (preferably in the presence of cuprous iodide, bis(triphenylphosphino)dichloropalladium and triethylamine). ) conducting an addition reaction to obtain a compound of formula (IIab) or a pharmaceutically acceptable salt thereof;
Obtaining a compound of formula (IIaab) or a pharmaceutically acceptable salt thereof by subjecting the compound of general formula (IIab) or a pharmaceutically acceptable salt thereof to an intramolecular cyclization reaction under basic conditions;
Reacting a compound of general formula (IIaab) or a pharmaceutically acceptable salt thereof with a halogenating reagent (for example, N-bromosuccinimide) to obtain a compound of formula (IIaabb) or a pharmaceutically acceptable salt thereof; ,
A compound of general formula (IIaabb) or a pharmaceutically acceptable salt thereof is combined with isopropenylboronic acid pinacol ester or 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (preferably [1,1' -bis(diphenylphosphino)ferrocene] in the presence of dichloropalladium and anhydrous tripotassium phosphate) to obtain a compound of formula (IIaaabb) or a pharmaceutically acceptable salt thereof; and IIaaabb) or a pharmaceutically acceptable salt thereof (preferably in a palladium on carbon and hydrogen atmosphere) to obtain a compound of formula (IIB) or a pharmaceutically acceptable salt thereof. ,
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
R ^t or R ^tt is halogen, preferably bromine;
R2 ^' is
and
R ² is an isopropyl group or
and
Ring A, R ¹ , R ³ , R ⁴ , n, s, J and k are as defined in general formula (IIB).

Technical plan 9
A method for preparing a compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof according to the present disclosure, the method comprising the following steps:
A compound of general formula (IIa) or a pharmaceutically acceptable salt thereof with a compound of general formula (IIbb) (preferably in the presence of anhydrous lithium chloride, potassium carbonate and tetrakis(triphenylphosphino)palladium) Obtaining a compound of general formula (IIB) or a pharmaceutically acceptable salt thereof by performing an indole synthesis reaction,
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
R ^t is halogen, preferably bromine;
Ring A, R ¹ to R ⁴ , n, s, J and k are as defined in general formula (IIB).

In the above synthesis proposal, the reagents providing acidic conditions include hydrogen chloride, a solution of hydrogen chloride in 1,4-dioxane, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluene. Sulfonic acids include, but are not limited to, Me ₃ SiCl and TMSOTf, preferably trifluoroacetic acid or hydrogen chloride in 1,4-dioxane.

In the above synthesis proposal, the reagents providing basic conditions include organic bases and inorganic bases, and the organic bases include triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and potassium acetate. , sodium acetate, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium ethylate, sodium tert-butoxide or potassium tert-butoxide. , sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide, preferably potassium hydroxide. tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate and sodium acetate.

In the above synthesis proposal, the reductive amination reaction is preferably carried out in the presence of a reducing agent and a weak acid, and the reducing agent includes sodium triacetoxyborohydride, sodium borohydride, lithium cyanoborohydride, Examples include, but are not limited to, sodium borohydride and acetyl sodium borohydride, and sodium triacetoxyborohydride is preferred, and the weak acid is preferably acetic acid.

The above synthesis scheme is preferably carried out in a solvent, and the solvents used include ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, These include, but are not limited to, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.

The present disclosure will be further described below in conjunction with Examples, but these Examples do not limit the scope of the present disclosure.

EXAMPLES The structures of compounds are determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ⁻⁶ (ppm). Bruker AVANCE NEO 500M is used for NMR measurement, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD), The internal standard is tetramethylsilane (TMS).

For MS measurement, liquid chromatograph mass spectrometer Agilent 1200/1290 DAD-6110/6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110/6120 Quadrupole MS), waters ACQuity UPLC-Q D/SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive) were used. .

For high performance liquid chromatography (HPLC) analysis, high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 were used.

A high performance liquid chromatograph Agilent 1260 DAD was used for chiral HPLC analysis measurements.

Preparative chromatographs Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 were used for preparative high performance liquid chromatography.

A preparative chromatograph Shimadzu LC-20AP was used for chiral fractionation.

Combiflash Rf200 (TELEDYNE ISCO) was used as the CombiFlash high-performance preparative chromatograph.

As the silica gel plate for thin layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used, and the specifications of the silica gel plate used for thin layer chromatography (TLC) were 0.15 mm to 0.2 mm. The specifications for product separation and purification by thin layer chromatography are 0.4 mm to 0.5 mm.

For silica gel column chromatography, 200 mesh to 300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the vector.

A microplate reader NovoStar (BMG, Germany) was used to measure the kinase average inhibition rate and IC ₅₀ value.

Known starting materials according to the present disclosure may be synthesized by employing or following known methods in the art, or may be synthesized by ABCR GmbH & Co. It may be purchased from companies such as KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dalui Chemicals, etc.

Unless otherwise specified in the examples, all reactions can be carried out in an argon or nitrogen atmosphere.

Argon or nitrogen atmosphere refers to an argon or nitrogen balloon with a volume of approximately 1 L connected to the reaction flask.

Hydrogen atmosphere refers to a hydrogen balloon with a volume of approximately 1 L connected to the reaction flask.

For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenation apparatus and a Seiran QL-500 type hydrogen generator or HC2-SS type hydrogenation apparatus were used.

In the hydrogenation reaction, the operation of evacuation and filling with hydrogen was generally repeated three times.

A CEM Discover-S 908860 type microwave reactor was used for the microwave reaction.

In the Examples, unless otherwise specified, solutions refer to aqueous solutions.

Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

Thin layer chromatography (TLC) was used to monitor the reaction progress in the examples, and the developing solvent used in the reaction, the eluent system for column chromatography to purify the compound, and the developing solvent system for thin layer chromatography A: n-hexane/ethyl acetate system, B: dichloromethane/methanol system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and is adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid. It's okay.

Example 1
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine 1
Step 1
2,6-dimethyl-4-((trimethylsilyl)ethynyl)pyridine 1c
4-bromo-2,6-dimethylpyridine 1a (5.0 g, 26.9 mmol, Shanghai Bidu Pharmaceutical), trimethylsilylethynyl 1b (8.0 g, 81.5 mmol, Shaoyuan Technology (Shanghai)), Cuprous iodide (550 mg, 2.89 mmol, Alfa Aesar (China)), bis(triphenylphosphino)dichloropalladium (1.0 g, 1.42 mmol, J&K) and triethylamine (8.15 g , 80.7 mmol) was dissolved in anhydrous N,N-dimethylformamide (100 mL) and reacted under nitrogen atmosphere at 45° C. with stirring for 16 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, ethyl acetate (100 mL) was added, filtered, washed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A. The title product 1c (5.3 g, yield: 97%) was obtained.
MS m/z (ESI): 204.0 [M+1].

Step 2
4-ethynyl-2,6-dimethylpyridine 1d
Compound 1c (5.3 g, 26.1 mmol) was dissolved in methanol (100 mL), and potassium carbonate (5.25 g, 38.0 mmol) was added. Stirred at room temperature for 2.0 hours. Filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give the title product 1d (1.7 g, yield: 49.7%).
^1H NMR (500 MHz, _CDCl3 ) δ 7.06 (s, 2H), 3.22 (s, 1H), 2.53 (s, 6H).

Step 3
3-(((benzyloxy)carbonyl)amino)-5,8-dihydro-1,7-naphthyridine-7(6H)-tert-butyl formate 1f
7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylic acid 1e (4.17 g, 15.0 mmol, Jiangsu Aikang Biotechnology), diphenyl phosphate Azide (4.35 g, 17.9 mmol, Shanghai Bidu Pharmaceutical) and N,N-diisopropylethylamine (2.72 g, 21.0 mmol) were dissolved in anhydrous toluene (85 mL). Stirred at room temperature for 1.0 hour under nitrogen atmosphere. Benzyl alcohol (8.0 g, 74.0 mmol, national drug) was added, and the mixture was stirred at 105° C. for 3.0 hours under a nitrogen atmosphere. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL x 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A. The title product 1f (5.5 g, yield: 95.7%) was obtained.
MS m/z (ESI): 383.9 [M+1].

Step 4
3-Amino-5,8-dihydro-1,7-naphthyridine-7(6H)-tert-butyl formate 1g
Compound 1f (6.8 g, 17.7 mmol) was dissolved in methanol (100 mL), and palladium on carbon (1.89 g, 1.77 mmol, 10% purity, Adamas) was added. The reaction was carried out under a hydrogen atmosphere at room temperature for 2.0 hours with stirring. Filtration and concentration under reduced pressure gave 1 g (4.42 g, yield: 100%) of the crude title product. The product was used directly in the next reaction without purification.
MS m/z (ESI): 250.0 [M+1].

Step 5
3-Amino-2-bromo-5,8-dihydro-1,7-naphthyridine-7(6H)-tert-butyl formate 1h
1 g (4.42 g, 17.7 mmol) of the original product compound was dissolved in N,N-dimethylformamide (120 mL), and N-bromosuccinimide (3.35 g, 18.8 mmol) was dissolved in Shaoyuan Technology ( (Shanghai)) was added and stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 1h (4.7 g, yield: 80.8%).
MS m/z (ESI): 328.0 [M+1].

Step 6
3-Amino-2((2,6-dimethylpyridin-4-yl)ethynyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-tert-butyl formate 1i
Compound 1h (1.35 g, 4.11 mmol), compound 1d (600 mg, 4.57 mmol), cuprous iodide (160 mg, 0.84 mmol, Alfa Aesar (China)), bis(tri) Phenylphosphino)dichloropalladium (290 mg, 0.41 mmol, J&K) and triethylamine (1.25 g, 12.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL) under a nitrogen atmosphere. The reaction was carried out at 40° C. for 16 hours with stirring. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL x 4), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B. The title product 1i (1.50 g, yield: 96.4%) was obtained.
MS m/z (ESI): 379.0 [M+1].

Step 7
tert-butyl 2-(2,6-dimethylpyridin-4-yl)-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridin-6-formate 1j
Compound 1i (1.40 g, 3.70 mmol) and potassium tert-butoxide (2.10 g, 18.7 mmol, Shaoyuan Technology (Shanghai)) were dissolved in anhydrous N-methylpyrrolidone (20 mL). The reaction was carried out under a nitrogen atmosphere at 40° C. for 16 hours with stirring. Add saturated aqueous ammonium chloride solution (100 mL), extract with ethyl acetate (80 mL x 4), combine the organic phases, wash with saturated sodium chloride solution (50 mL x 4), concentrate under reduced pressure, and remove the residue. was purified by silica gel column chromatography with eluent system B to give the title product 1j (900 mg, yield: 64.3%).
MS m/z (ESI): 378.9 [M+1].

Step 8
3-Bromo-2-(2,6-dimethylpyridin-4-yl)-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridin-6-formic acid tert -Butyl 1k
Compound 1j (900 mg, 2.38 mmol) was dissolved in N,N-dimethylformamide (20 mL), cooled to 0 °C, and N-bromosuccinimide (430 mg, 2.42 mmol, Shaoyuan Technology (Shanghai)). ) was added. Stirred at 0°C for 2.0 hours. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL x 4), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B. The title product 1k (1.08 g, yield: 99.3%) was obtained.
MS m/z (ESI): 457.0 [M+1].

Step 9
2-(2,6-dimethylpyridin-4-yl)-3-(prop-1-en-2-yl)-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][ 1,7] tert-butyl naphthyridine-6-formate 1l
Compound 1k (1.08 g, 2.36 mmol), isopropenylboronic acid pinacol ester (1.5 g, 8.93 mmol, Shaoyuan Technology (Shanghai)), [1,1'-bis(diphenylphosphino) ) Ferrocene] dichloropalladium (180 mg, 0.25 mmol, Shanghai Bidu Pharmaceutical) and anhydrous tripotassium phosphate (1.50 g, 7.07 mmol) were added to anhydrous dioxane (16.0 mL) and water (4. 0 mL) and reacted under nitrogen atmosphere at 80° C. with stirring for 16 hours. The reaction solution was cooled to room temperature, water (15 mL) was added, extracted with ethyl acetate (30 mL x 4), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system. B to obtain 1 l (900 mg, yield: 91.1%) of the title product.
MS m/z (ESI): 419.0 [M+1].

Step 10
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine-6-formic acid tert -Butyl 1m
Compound 1 l (900 mg, 2.15 mmol) was dissolved in methanol (30 mL), and palladium on carbon (500 mg, 0.47 mmol, 10% purity, Adamas) was added. The reaction was carried out under a hydrogen atmosphere at room temperature with stirring for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in methanol (30 mL), and palladium on carbon (500 mg, 0.47 mmol, 10% purity, Adamas) was added. The reaction was carried out under a hydrogen atmosphere at room temperature with stirring for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1m (350 mg, yield: 38.7%). .
MS m/z (ESI): 421.0 [M+1].

Step 11
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine 1
Compound 1m (65.0 mg, 0.15 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL). Stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 7 M ammonia/methanol solution (5 mL) was added to the residue. It was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (column: Boston Phlex Prep C18, 5 μm, 30 mm x 150 mm, mobile phase: A-water (10 mmol ammonium bicarbonate): B- acetonitrile, 28% to 48% acetonitrile, 15 min gradient elution, flow rate: 30 mL/min) to give the title product 1 (26.0 mg, yield: 52.5%).
MS m/z (ESI): 321.2 [M+1].
¹ H NMR (500 MHz, CD ₃ OD) δ 7.47 (s, 1H), 7.27 (s, 2H), 4.19 (s, 2H), 3.41 (m, 1H), 3. 18 (t, 2H), 3.04 (t, 2H), 2.59 (s, 6H), 1.54 (d, 6H).

Example 2
2-(2,6-dimethylpyridin-4-yl)-3,6-diisopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine
2
Step 1
2-(2,6-dimethylpyridin-4-yl)-3,6-diisopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine
2
Compound 1 (50 mg, 0.16 mmol) and 2-iodopropane (100 mg, 0.59 mmol) were dissolved in acetonitrile (5 mL), and potassium carbonate (100 mg, 0.72 mmol) was added. The mixture was stirred at 80°C for 2.0 hours. Filtered and concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: Boston Phlex Prep C18, 5 μm, 30 mm x 150 mm, mobile phase: A-water (10 mmol ammonium bicarbonate) :B-acetonitrile, 40% to 60% acetonitrile, gradient elution over 15 minutes, flow rate: 30 mL/min) to give the title product 2 (28.0 mg, yield: 49.5%).
MS m/z (ESI): 363.2 [M+1].
¹ H NMR (500 MHz, CD ₃ OD) δ 7.49 (s, 1H), 7.27 (s, 2H), 3.98 (s, 2H), 3.42 (m, 1H), 3. 08 (t, 2H), 3.01 (m, 1H), 2.93 (t, 2H), 2.59 (s, 6H), 1.54 (d, 6H), 1.26 (d, 6H) ).

Example 3
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinoline -6-amine 3
Step 1
(3-nitro-5,6,7,8-tetrahydroquinolin-7-yl)benzyl carbamate 3c-1
(3-nitro-5,6,7,8-tetrahydroquinolin-5-yl)benzyl carbamate 3c-2
Benzyl (3-oxycyclohexyl)carbamate 3a (3.0 g, 12.1 mmol, Shanghai Bidu Pharmaceutical) and 1-methyl-3,6-dinitropyridin-2(1H)-one 3b (3.0 g , 15.1 mmol, Nanjing Yakushi) was dissolved in a 7 M ammonia/methanol solution (15 mL) and methanol (15 mL), and the mixture was sealed and stirred at 90° C. for 2.0 hours. The reaction was concentrated under reduced pressure, the residue was dissolved in dichloromethane (150 mL), washed with water (100 mL) and saturated sodium chloride solution (100 mL), the organic phase was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (150 mL). Purification by silica gel column chromatography with eluent system A gave a mixture of title products 3c-1 and 3c-2 (3.5 g, yield: 88.1%).
MS m/z (ESI): 327.9 [M+1].

Step 2
Benzyl (3-amino-5,6,7,8-tetrahydroquinolin-7-yl)carbamate 3d-1
(3-Amino-5,6,7,8-tetrahydroquinolin-5-yl)benzyl carbamate 3d-2
A mixture of compounds 3c-1 and 3c-2 (8.0 g, 24.4 mmol) was dissolved in ethanol (100 mL) and water (25 mL). Iron powder (12.0 g, 215 mmol, national drug) and ammonium chloride (13.0 g, 241 mmol) were added. The reaction was carried out at 80° C. for 3.0 hours with stirring. The reaction was cooled to room temperature, concentrated under reduced pressure, water (200 mL) was added, extracted with ethyl acetate (200 mL x 4), the organic phases were combined and concentrated under reduced pressure to yield the title product 3d- A crude product (7.26 g, yield: 99.9%) of a mixture of 1 and 3d-2 was obtained. The crude product was used as it was in the next reaction without purification.
MS m/z (ESI): 298.0 [M+1].

Step 3
Benzyl 2-(3-amino-2-bromo-5,6,7,8-tetrahydroquinolin-7-yl)carbamate 3e
A crude mixture of compounds 3d-1 and 3d-2 (7.3 g, 24.6 mmol) was dissolved in N,N-dimethylformamide (100 mL), and N-bromosuccinimide (4.50 g, 25.6 mmol) was dissolved in N,N-dimethylformamide (100 mL). 3 mmol of Shaoyuan Technology (Shanghai)) was added. Stirred at 0°C for 2.0 hours. The reaction was warmed to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title product 3e (3.5 g, yield: 37.9%). Obtained.
MS m/z (ESI): 376.0 [M+1].

Step 4
Benzyl (3-amino-2((2,6-dimethylpyridin-4-yl)ethynyl)-5,6,7,8-tetrahydroquinolin-7-yl)carbamate 3f
Compound 3e (1.0 g, 2.66 mmol), compound 1d (400 mg, 3.05 mmol), cuprous iodide (105 mg, 0.55 mmol, Alfa Aesar (China)), bis(tri) Phenylphosphino) dichloropalladium (190 mg, 0.27 mmol, J&K) and triethylamine (810 mg, 8.02 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL) and incubated at 40 °C under a nitrogen atmosphere. The mixture was reacted with stirring for 16 hours. The reaction solution was cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (50 mL x 4), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system. B to give the title product 3f (300 mg, yield: 26.5%).
MS m/z (ESI): 426.9 [M+1].

Step 5
(2-((2,6-dimethylpyridin-4-yl)ethynyl)-3-(2,2,2-trifluoroacetamide)-5,6,7,8-tetrahydroquinolin-7-yl)carbamic acid benzyl 3g
Compound 3f (580 mg, 1.36 mmol) was dissolved in anhydrous dioxane (20 mL), and potassium carbonate (500 mg, 3.62 mmol) and trifluoroacetic anhydride (450 mg, 2.14 mmol, adamas) were added. added. Stirred at room temperature for 3.0 hours. Water (30 mL) was added, extracted with ethyl acetate (30 mL x 4), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title product. 3g (270 mg, yield: 38.0%) was obtained.
MS m/z (ESI): 522.9 [M+1].

Step 6
(2-(2,6-dimethylpyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinolin-6-yl)benzyl carbamate 3h
3 g (270 mg, 0.52 mmol) of the compound, cuprous iodide (100 mg, 0.53 mmol, Alfa Aesar (China)) and triethylamine (200 mg, 1.98 mmol) in anhydrous N,N-dimethyl It was dissolved in formamide (10 mL) and reacted under a nitrogen atmosphere at 105° C. with stirring for 3.0 hours. Water (20 mL) was added, extracted with ethyl acetate (20 mL x 4), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product. 3h (220 mg, yield: 99.8%) was obtained.
MS m/z (ESI): 426.9 [M+1].

Step 7
(3-bromo-2-(2,6-dimethylpyridin-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinolin-6-yl)benzyl carbamate 3i
Compound 3h (220 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (5.0 mL), cooled to 0°C, and N-bromosuccinimide (95 mg, 0.53 mmol, Shaoyuan Technology ( Shanghai)) was added. Stirred at room temperature for 2.0 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system B to give the title product 3i (225 mg, yield: 86.5%).
MS m/z (ESI): 505.8 [M+1].

Step 8
(2-(2,6-dimethylpyridin-4-yl)-3-(prop-1-en-2-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b] Benzyl quinolin-6-yl)carbamate 3j
Compound 3i (225 mg, 0.45 mmol), isopropenylboronic acid pinacol ester (200 mg, 1.19 mmol, Shaoyuan Technology (Shanghai)), [1,1'-bis(diphenylphosphino)ferrocene] dichloro Palladium (35 mg, 0.05 mmol, Shanghai Bidu Pharmaceutical) and anhydrous tripotassium phosphate (285 mg, 1.34 mmol) were dissolved in anhydrous dioxane (4.0 mL) and water (1.0 mL), The reaction was carried out under a nitrogen atmosphere at 80° C. for 16 hours with stirring. The reaction solution was cooled to room temperature, water (15 mL) was added, extracted with ethyl acetate (20 mL x 4), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system. Purification in A gave the title product 3j (110 mg, yield: 53%).
MS m/z (ESI): 467.0 [M+1].

Step 9
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinolin-6-amine 3k
Compound 3j (110 mg, 0.24 mmol) was dissolved in methanol (10 mL), and palladium on carbon (200 mg, 0.19 mmol, 10% purity, Adamas) was added. The reaction was allowed to proceed under a hydrogen atmosphere at room temperature for 18 hours with stirring. Filtration and concentration under reduced pressure gave the crude title product 3k (50 mg, yield: 63.4%), which was used directly in the next reaction without purification.
MS m/z (ESI): 335.0 [M+1].

Step 10
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-N-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]quinoline -6-amine 3
Crude compound 3k (50.0 mg, 0.15 mmol) and dihydrofuran-3(2H)-one (20 mg, 0.23 mmol, Shaoyuan Technology (Shanghai)) were added to dichloromethane (5.0 mL). ) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (70 mg, 0.33 mmol, Shaoyuan Technology (Shanghai)) was added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: Welch Ultimate ): B-acetonitrile, 20% to 95% acetonitrile, gradient elution over 20 minutes, flow rate: 30 mL/min) to give the title product 3 (5.0 mg, yield: 8.3%).
MS m/z (ESI): 405.0 [M+1].
^1H NMR (500 MHz, _CD3OD ) δ 7.45 (s, 1H), 7.27 (s, 2H), 4.01-3.94 (m, 2H), 3.82 (m, 1H) ), 3.73 (m, 1H), 3.62 (m, 1H), 3.46-3.39 (m, 2H), 3.15 (m, 1H), 3.04-3.00 ( m, 2H), 2.84 (m, 1H), 2.58 (s, 6H), 2.28-2.20 (m, 2H), 1.85 (m, 1H), 1.67 (m , 1H), 1.54 (d, 6H).

Example 4
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-6-(2-(6-(piperazin-4-yl)pyridin-3-yl)ethyl)-5,6,7,8 -Tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine 4
Step 1
tert-butyl 4-(5-(2-(hydroxyethyl)pyridin-2-yl)piperazine-1-carboxylate 4b
tert-butyl 4-(5-(2-methoxy-2-oxyethyl)pyridin-2-yl)piperazine-1-carboxylate 4a (120 mg, 0.36 mmol, on page 37 of the specification of document “WO2018138356 A1 "obtained by the synthesis method of compound 4a") was dissolved in anhydrous tetrahydrofuran (5.0 mL), cooled to 0 °C, and lithium borohydride (16 mg, 0.74 mmol, Japanese medicine) was added. Ta. The reaction was allowed to proceed at room temperature for 16 hours with stirring. Add sodium sulfate decahydrate, stir for 30 minutes, filter, wash, concentrate the filtrate under reduced pressure, and purify the residue by silica gel thin layer chromatography with developing solvent system A to give the title product 4b. (110 mg, yield: 100%) was obtained.
MS m/z (ESI): 307.8 [M+1].

Step 2
tert-butyl 4-(5-(2-((methylsulfonyl)oxy)ethyl)pyridin-2-yl)piperazine-1-carboxylate 4c
Compound 4b (140 mg, 0.46 mmol), methanesulfonyl chloride (70 mg, 0.61 mmol, national drug), and triethylamine (90 mg, 0.89 mmol) were dissolved in dichloromethane (5.0 mL). Stirred at 0°C for 2.0 hours. Water (20 mL) was added to the reaction solution, extracted with dichloromethane (20 mL x 3), the organic phases were combined and concentrated under reduced pressure to obtain the crude title product 4c (175 mg, yield: 99.7). %) was obtained. The product was used directly in the next step without purification.
MS m/z (ESI): 385.9 [M+1].

Step 3
tert-butyl 4-(5-(2-iodoethyl)pyridin-2-yl)piperazine-1-carboxylate 4d
Crude compound 4c (175 mg, 0.45 mmol) and sodium iodide (200 mg, 1.33 mmol, adamas) were dissolved in acetone (10 mL). The mixture was stirred at 60°C for 16 hours. Concentrate under reduced pressure, add water (20 mL) to the residue, extract with ethyl acetate (20 mL x 3), combine the organic phases, concentrate under reduced pressure, and filter the residue by silica gel column chromatography with eluent. Purification with System A gave the title product 4d (140 mg, yield: 73.9%).
MS m/z (ESI): 417.8 [M+1].

Step 4
4-(5-(2-(2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1 ,7] tert-butyl naphthyridin-6-yl)ethyl)pyridin-2-yl)piperazine-1-carboxylate 4e
Compound 4d (70 mg, 0.17 mmol), compound 1 (30 mg, 0.094 mmol) and cesium carbonate (100 mg, 0.31 mmol, Shaoyuan Technology (Shanghai)) were mixed with dimethyl sulfoxide (3.0 mL). ) and reacted at 100°C for 4.0 hours with stirring. The reaction solution was washed with ethyl acetate (30 mL), water (10 mL) and saturated sodium chloride solution (10 mL x 2), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography. Purification with developing solvent system A gave the title product 4e (40 mg, yield: 70%).
MS m/z (ESI): 610.3 [M+1].

Step 5
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-6-(2-(6-(piperazin-4-yl)pyridin-3-yl)ethyl)-5,6,7,8 -Tetrahydro-1H-pyrrolo[3,2-b][1,7]naphthyridine 4
Compound 4e (70.0 mg, 0.11 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL). Stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 7 M ammonia/methanol solution (5 mL) was added to the residue. It was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (column: Sharpsil-T Prep C18, 5 μm, 30 mm x 150 mm, mobile phase: A - water (10 mmol ammonium bicarbonate): B -acetonitrile, 30% to 95% acetonitrile, gradient elution over 18 minutes, flow rate: 30 mL/min) to give the title product 4 (25.0 mg, yield: 42.7%).
MS m/z (ESI): 510.3 [M+1].
^1H NMR (500 MHz, _CD3OD ) δ 8.07 (d, 1H), 7.58 (dd, 1H), 7.50 (s, 1H), 7.28 (s, 2H), 6. 83 (d, 1H), 3.95 (s, 2H), 3.50-3.48 (m, 4H), 3.42 (m, 1H), 3.11 (t, 2H), 2.99 -2.97 (m, 4H), 2.93 (t, 2H), 2.91-2.87 (m, 2H), 2.85-2.81 (m, 2H), 2.59 (s , 6H), 1.55 (d, 6H).

Example 5
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-6-((5-(piperazin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro -1H-pyrrolo[3,2-b][1,7]naphthyridine 5
Step 1
(5-bromopyridin-2-yl)methylacetic acid 5b
5-Bromo-2-methylpyridine 5a (4.0 g, 23.3 mmol, Shaoyuan Technology (Shanghai)) was dissolved in dichloromethane (50 mL), cooled to 0 °C, and dissolved in 3-chloroperbenzoic acid (6 .1 g, 35.3 mmol, Japanese medicine) was added thereto, and the mixture was reacted with stirring at room temperature for 16 hours. The reaction was washed with saturated sodium bicarbonate solution (50 mL) and the organic phase was concentrated under reduced pressure. The residue was dissolved in acetic anhydride (16 mL) and heated under reflux for 1.0 hour. The reaction was quenched by adding ethanol, and the reaction solution was concentrated under reduced pressure. The residue was neutralized with saturated potassium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL x 2), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using the eluent system. Purification in A gave the title product 5b (2.1 g, yield: 39.2%).
MS m/z (ESI): 229.6 [M+1].

Step 2
tert-butyl 4-(6-(acetoxymethyl)pyridin-3-yl)piperazine-1-carboxylate 5c
Compound 5b (1.0 g, 4.35 mmol), tert-butyl piperazine-1-carboxylate (1.62 g, 8.7 mmol, Shaoyuan Technology (Shanghai)), cesium carbonate (4.3 g, 13.2 mmol, Shaoyuan Technology (Shanghai)), tris(dibenzylideneacetone)dipalladium (399 mg, 0.44 mmol, Shanghai Bidu Pharmaceutical), and 1,1'-binaphthyl-2,2'-bis ( Diphenylphosphino) (542 mg, 0.87 mmol, Shanghai Bidu Pharmaceutical) was dissolved in toluene (30 mL). The reaction was carried out under a nitrogen atmosphere at 90° C. for 12 hours with stirring. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 5c (1.2 g, yield: 82.3%).
MS m/z (ESI): 335.9 [M+1].

Step 3
tert-butyl 4-(6-(hydroxymethyl)pyridin-3-yl)piperazine-1-carboxylate 5d
Compound 5c (390 mg, 1.16 mmol) and potassium hydroxide monohydrate (150 mg, 3.57 mmol, Japanese medicine) were dissolved in tetrahydrofuran (9.0 mL) and water (3.0 mL). . Stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL x 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A. The title product 5d (240 mg, yield: 70.4%) was obtained.
MS m/z (ESI): 294.0 [M+1].

Step 4
4-(6-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl)-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1, 7] tert-butyl naphthyridin-6-yl)methyl)pyridin-3-yl)piperazine-1-carboxylate 5e
Compound 5d (150 mg, 0.51 mmol), methanesulfonyl chloride (60 mg, 0.52 mmol, national drug) and triethylamine (55 mg, 0.54 mmol) were dissolved in dichloromethane (3.0 mL), The reaction was allowed to proceed at a temperature of 2.0 hours with stirring. The reaction solution was added dropwise to a solution of Compound 1 (80 mg, 0.25 mmol) and potassium carbonate (100 mg, 0.72 mmol) in acetonitrile (5.0 mL), and the reaction was carried out with stirring at 70°C for 2.0 hours. I let it happen. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL x 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography using developing solvent system A. , the title product 5e (100 mg, yield: 67.2%) was obtained.
MS m/z (ESI): 596.3 [M+1].

Step 5
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-6-((5-(piperazin-1-yl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydro -1H-pyrrolo[3,2-b][1,7]naphthyridine 5
Compound 5e (100.0 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL). Stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 7 M ammonia/methanol solution (5 mL) was added to the residue. It was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (column: Sharpsil-T Prep C18, 5 μm, 30 mm x 150 mm, mobile phase: A - water (10 mmol ammonium bicarbonate): B -acetonitrile, 26% to 95% acetonitrile, gradient elution over 18 minutes, flow rate: 30 mL/min) to give the title product 5 (15.0 mg, yield: 18.0%).
MS m/z (ESI): 496.3 [M+1].
^1H NMR (500 MHz, _CD3OD ) δ 8.24 (d, 1H), 7.51-7.47 (m, 3H), 7.26 (s, 2H), 3.86-3.85 (m, 4H), 3.39 (m, 1H), 3.27-3.25 (m, 4H), 3.09-3.04 (m, 6H), 2.90-2.88 (m , 2H), 2.59 (s, 6H), 1.51 (d, 6H).

Example 6
2-(2,6-dimethylpyridin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][ 1,7] Naphthyridine 6
Step 1
2-(2,6-dimethylpyridin-4-yl)-7,8-dihydro-1H-pyrrolo[3,2-b][1,7]naphthyridine-1,6(5H)-dicarboxylic acid di-tert -Butyl 6a
Compound 1j (1.59 g, 4.20 mmol), di-tert-butyl dicarbonate (2.0 g, 9.16 mmol, Shaoyuan Technology (Shanghai)), 4-dimethylaminopyridine (100 mg, 0 .81 mmol, adamas) and triethylamine (3.0 g, 29.7 mmol) were dissolved in tetrahydrofuran (30 mL) and reacted with stirring at room temperature for 16 hours. Water (60 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL x 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A. The title product 6a (1.35 g, yield: 67.1%) was obtained.
MS m/z (ESI): 479.0 [M+1].

Step 2
3-Bromo-2-(2,6-dimethylpyridin-4-yl)-7,8-dihydro-1H-pyrrolo[3,2-b][1,7]naphthyridin-1,6(5H)-dicarvone Di-tert-butyl acid 6b
Compound 6a (1.35 g, 2.82 mmol) was dissolved in N,N-dimethylformamide (20 mL), cooled to 0 °C, and N-bromosuccinimide (600 mg, 3.37 mmol, Shaoyuan Technology ( Shanghai)) was added. Stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 6b (1.05 g, yield: 66.8%).
MS m/z (ESI): 556.9 [M+1].

Step 3
3-(3,6-dihydro-2H-pyran-4-yl)-2-(2,6-dimethylpyridin-4-yl)-7,8-dihydro-1H-pyrrolo[3,2-b][ 1,7] Naphthyridine-1,6(5H)-dicarboxylic acid di-tert-butyl 6c
Compound 6b (100 mg, 0.18 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (50 mg, 0.24 mmol, Shaoyuan Technology (Shanghai)), [1,1' -bis(diphenylphosphino)ferrocene] dichloropalladium (20 mg, 0.03 mmol, Shanghai Bidu Pharmaceutical) and anhydrous tripotassium phosphate (120 mg, 0.57 mmol) were mixed with dioxane (3.0 mL) and water. (1.0 mL) and reacted under nitrogen atmosphere at 80° C. with stirring for 16 hours. The reaction solution was cooled to room temperature, water (15 mL) was added, extracted with ethyl acetate (20 mL x 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system. Purification in A gave the title product 6c (90 mg, yield: 89.5%).
MS m/z (ESI): 561.0 [M+1].

Step 4
2-(2,6-dimethylpyridin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-1H-pyrrolo[3,2-b][1,7] Di-tert-butyl naphthyridine-1,6(5H)-dicarboxylate 6d
Compound 6c (90 mg, 0.16 mmol) was dissolved in methanol (10 mL), and palladium on carbon (100 mg, 0.094 mmol, 10% purity, Adamas) was added. The reaction was carried out under a hydrogen atmosphere at room temperature with stirring for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 6d (80 mg, yield: 88.6%). The product was used directly in the next reaction without purification.
MS m/z (ESI): 563.0 [M+1].

Step 5
2-(2,6-dimethylpyridin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b][ 1,7] Naphthyridine 6
Crude compound 6d (80.0 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 7 M ammonia/methanol solution (5 mL) was added to the residue. It was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (column: Sharpsil-T Prep C18, 5 μm, 30 mm x 150 mm, mobile phase: A - water (10 mmol ammonium bicarbonate): B -acetonitrile, 28% to 95% acetonitrile, gradient elution over 18 minutes, flow rate: 30 mL/min) to give the title product 6 (14 mg, yield: 27.2%).
MS m/z (ESI): 363.3 [M+1].
¹ H NMR (500 MHz, CD ₃ OD) δ 7.49 (s, 1H), 7.28 (s, 2H), 4.20 (s, 2H), 4.08-4.05 (m, 2H ), 3.59-3.54 (m, 2H), 3.26 (m, 1H), 3.21-3.19 (m, 2H), 3.06-3.04 (m, 2H), 2.82-2.73 (m, 2H), 2.59 (s, 6H), 1.66-1.62 (m, 2H).

Example 7
4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine- 6-yl)methyl)bicyclo[2.2.2]octan-1-amine 7
Step 1
(4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine tert-butyl-6-yl)methyl)bicyclo[2.2.2]octan-1-yl)carbamate 7b
Compound 1 (1.05 g, 3.28 mmol) and tert-butyl (4-formylbicyclo[2.2.2]octan-1-yl)aminoformate 7a (1.60 g, 6.32 mmol, Ref. "Prepared by the synthesis method of intermediate A on page 67 of the specification of WO2013003383A1")
1684720024745_96
(20 mL) and N,N-dimethylformamide (4.0 mL), 1 drop of acetic acid was added, and the mixture was reacted with stirring at room temperature for 2.0 hours. Sodium triacetoxyborohydride (1.50 g, 7.08 mmol) was added, and the mixture was reacted with stirring at 60° C. for 16 hours. Concentrate under reduced pressure, add water (50 mL) to the residue, extract with ethyl acetate (50 mL x 4), combine the organic phases, concentrate under reduced pressure, and filter the residue by silica gel column chromatography with eluent. Purification on system B gave the title product 7b (1.05 g, yield: 57.4%).
MS m/z (ESI): 558.3 [M+1].

Step 2
4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine- 6-yl)methyl)bicyclo[2.2.2]octan-1-amine 7
Compound 7b (1.05 g, 0.11 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4.0 mL). Stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 7 M ammonia/methanol solution (20 mL) was added to the residue. It was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (column: Waters XBridge C18, 5 μm, 30 mm x 150 mm, mobile phase: A - aqueous phase (0.5% ammonium hydroxide): B-acetonitrile (0.5% ammonium hydroxide), 80% to 95% acetonitrile, gradient elution over 18 minutes, flow rate: 30 mL/min), title product 7 (330 mg, yield: 38.3%) ) was obtained.
MS m/z (ESI): 458.3 [M+1].
¹ H NMR (500 MHz, CD ₃ OD) δ 7.45 (s, 1H), 7.27 (s, 2H), 3.86 (s, 2H), 3.42 (m, 1H), 3. 02-3.00 (m, 2H), 2.83-2.80 (m, 2H), 2.59 (s, 6H), 2.30 (s, 2H), 1.66-1.62 ( m, 6H), 1.60-1.57 (m, 6H), 1.53 (d, 6H).

Example 8
2-(2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3,2-b][1,7]naphthyridine-6 -yl) acetamide 8
Compound 1 (300 mg, 0.94 mmol), 2-bromoacetamide (200 mg, 1.45 mmol, Shaoyuan Technology (Shanghai)) and 1,8-diazabicyclo[5.4.0]undec-7-ene (500 mg, 1.99 mmol, adamas)
1684720024745_98
(10 mL) and reacted at room temperature for 6.0 hours with stirring. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: Boston Phlex Prep C18, 5 μm, 30 mm x 150 mm, mobile phase: A-aqueous phase (10 mmol of ammonium hydrogen carbonate) ): B-acetonitrile, 20% to 80% acetonitrile, gradient elution over 20 minutes, flow rate: 30 mL/min) to give the title product 8 (120 mg, yield: 34%).
MS m/z (ESI): 378.0 [M+1].
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.14 (s, 1H), 7.43 (s, 1H), 7.30 (d, 1H), 7.20 (s, 2H), 7 .17 (d, 1H), 3.78 (s, 2H), 3.34 (s, 6H), 3.31 (m, 1H), 3.11 (s, 2H), 3.01-2. 99 (m, 2H), 2.78-2.76 (m, 2H), 1.50 (d, 6H).

Example 9
2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3 ,2-b][1,7]naphthyridine 9
Step 1
7,8-dimethyl-6-(3-methylbut-1-yn-1-yl)-[1,2,4]triazolo[1,5-a]pyridine 9b
6-Bromo-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine 9a (760 mg, 3.36 mmol, intermediate F on page 140 of the specification of patent application WO2018005586A1 -4) and 3-methyl-1-butyne (500 mg, 7.34 mmol, Acros), cuprous iodide (130 mg, 0.682 mmol, Alfa) , bistriphenylphosphinodichloropalladium (240 mg, 0.341 mmol, ADAMAS), and triethylamine (1.0 g, 10.0 mmol) were dissolved in N,N-dimethylformamide (15 mL) under a nitrogen atmosphere. Stirred at 60 ^° C. for 30 hours. Quenched by adding water (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A, The title product 9b (650 mg, yield: 90.6%) was obtained.
MS m/z (ESI): 214.0 [M+1].

Step 2
2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H-pyrrolo[3 ,2-b][1,7]tert-butyl naphthyridine-6-carboxylate 9c
Compound 1h (1.0 g, 3.05 mmol) and compound 9b (650 mg, 3.05 mmol) were dissolved in dimethylacetamide (20 mL), anhydrous lithium chloride (130 mg, 3.07 mmol), potassium carbonate. (1.27 g, 9.20 mmol) and tetrakis(triphenylphosphino)palladium (360 mg, 0.31 mmol, adamas) were added and reacted at 115°C for 20 hours, and the reaction solution was cooled to room temperature. Water (60 mL) was added, extracted with ethyl acetate (50 mL x 3), the organic phases were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title product. 9c (700 mg, yield: 49.9%) was obtained.
MS m/z (ESI): 461.0 [M+1].

Step 3
2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5,6,7,8-tetrahydro-1H-pyrrolo[3 ,2-b][1,7]naphthyridine 9
Compound 9c (700 mg, 1.52 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. It was concentrated and the residue was purified by silica gel column chromatography with eluent system B to obtain the crude product. The crude product was purified with a chiral column (column: CHIRALPAK IF 20 mm x 250 mm, mobile phase: An-hexane, B-ethanol (containing 10 mM _NH3 ), flow rate: 20 mL/min, detection wavelength 214 nm & 254 nm) to give the title product 9 (120 mg, 21.9%).
MS m/z (ESI): 361.0 [M+1].
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.30 (s, 1H), 8.84 (s, 1H), 8.50 (s, 1H), 7.56 (s, 1H), 4 .32 (s, 2H), 3.39-3.37 (m, 2H), 3.31 (s, 1H), 3.14-3.12 (m, 2H), 2.91 (m, 1H) ), 2.60 (s, 3H), 2.15 (s, 3H), 1.37 (d, 6H).

Example 10
2-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1,5,7,8-tetrahydro-6H- Pyrrolo[3,2-b][1,7]naphthyridin-6-yl)acetamide 10
Compound 9 (85 mg, 0.24 mmol), 2-bromoacetamide (60 mg, 0.43 mmol, Shaoyuan Technology (Shanghai)) and 1,8-diazabicyclo[5.4.0]undec-7-ene (120 mg, 0.48 mmol, adamas)
1684720024745_101
(5.0 mL) and reacted at room temperature for 6.0 hours with stirring. The reaction solution was concentrated under reduced pressure, and the residue was purified using a chiral column (column: CHIRALPAK IF 20 mm x 250 mm, mobile phase: A-n-hexane, B-ethanol (containing 10 mM _NH3 ), flow rate :20 mL/min, detection wavelength 214 nm & 254 nm), the title product 10 (20 mg, 20.3%) was obtained.
MS m/z (ESI): 418.0 [M+1].
^1H NMR (500 MHz, CD3OD) δ 8.67 (s, 1H), 8.43 (s, 1H), 7.51 (s, 1H), 3.98 (s, 2H), 3.32 ( s, 2H), 3.22 (m, 1H), 3.15-3.12 (m, 2H), 2.96-2.93 (m, 2H), 2.67 (s, 3H), 2 .26 (s, 3H), 1.34 (d, 6H).

Biological Evaluation The present disclosure will be further described below in conjunction with test examples, but these Examples do not limit the scope of the present disclosure.

Test Example 1 Inhibitory effect of the compound according to the present disclosure on the human TLR7 activation pathway 1. Experimental materials and equipment 1. HEK-Blue ^TM hTLR7 cells (Invivogen)
2. Resiquimod (R848/Resiquimod, Invivogen)
3. Basic phosphatase detection medium (Quanti-Blue Detection, Invivogen)
4. Blasticidin (Invivogen)
5. Bleomycin (Zeocin, Invivogen)
6. Neomycin (Normocin, Invivogen)
7. DMEM/High Glucose Medium (DMEM/HIGH Glucose, GE Healthcare)
8. Fetal bovine serum (FBS, Gibco)
9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)
10. Sterile pure water (homemade by Shanghai Hengrui)
11, 15 mL centrifuge tube (Corning)
12, 96-well combination plate (Corning)
13, 96-well flat bottom cell culture plate (Corning)
14. Thermoscientific cell incubator (Thermo scientific)
15. Temperature chamber (Shanghai Yicheng Scientific Instruments Co., Ltd.)
16, PHERAstar FS microplate reader (BMG Labtech)
2. Experimental Procedures HEK-Blue ^TM hTLR7 cells were purchased from Invivogen, and these cells were used to cotransfer the human Toll-like receptor 7 (TLR7) gene and secreted basic phosphatase-containing reporter gene (SEAP) into HEK293 cells. The basic phosphatase reporter gene (SEAP) is under the control of the IFN-β minimal promoter, which contains five NF-kB and AP-1 binding sites, and is activated when TLR7 is activated by agonists. , downstream NF-kB and AP-1 cause SEAP secretion, and after adding an antagonistic compound, the above pathway is inhibited and SEAP secretion is reduced. Activity was evaluated.

20 mM of test compound dissolved in 100% DMSO was stepped to 2000 μM, 400 μM, 80 μM, 16 μM, 3.2 μM, 0.64 μM, 0.128 μM, 0.0256 μM with 100% DMSO. After dilution, blank wells were made into 100% DMSO and diluted 20-fold in DMEM/high glucose medium (complete medium, hereinafter) containing 10% inactivated FBS. Resiquimod was diluted to 10 μM with sterile water. Resiquimod 10 μM diluted in sterile water was added at 20 μL/well to a 96-well cell culture plate. Compounds diluted in the above complete medium and 100% DMSO were then added to the wells containing resiquimod at 20 μL per well. Negative control wells received 20 μL of sterile water and 20 μL of 100% DMSO diluted in complete medium.

HEK-Blue ^™ hTLR7 cells were cultured in DMEM/high glucose medium containing 10% inactivated FBS, 100 μg/mL neomycin, 10 μg/mL blasticidin, and 100 μg/mL bleomycin. Take cells with good growth and 70% to 80% growth, discard the growth medium, wash the cells once by adding 5 mL to 10 mL of prewarmed PBS at 37 °C, and add 2 mL to 2 mL of prewarmed PBS. Add 5 mL, incubate at 37°C for 1 to 2 minutes, scatter the cells with a pipette, transfer the cells to a 15 mL centrifuge tube, count the cells, and bring the cell density to 4.8 with complete medium. The concentration was adjusted to ×10 ⁵ /mL. 160 μL of the cell suspension with adjusted density was placed in the above 96-well cell culture plate, and the final number of cells in each well was 76,500/well, the final concentration of resiquimod was 1 μM, and the final concentration of each test compound was 10,000. nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM. The cells were incubated in an incubator at 37°C and 5% _CO2 for 20 hours, then 20 μL of the supernatant was added to 180 μL of the prepared basic phosphatase detection medium and incubated in the dark in an incubator at 37°C. After incubation for 120 minutes, the absorbance value of OD620 was read using a microplate reader. The inhibition rate was calculated using the following formula:
Inhibition rate = {1 - (OD _{test compound} - OD _{negative control well} ) / (OD _{blank well} - OD _{negative control well} )} x 100%
An inhibition curve was drawn using Graphpad Prism software according to each concentration of the compound and the corresponding inhibition rate, and the IC ₅₀ value, which is the concentration of the compound at which the inhibition rate was 50%, was calculated as shown in Table 1.

Conclusion: The compounds according to the present disclosure have an inhibitory effect on the TLR7 pathway.

Test Example 2 Inhibitory effect of compounds according to the present disclosure on human TLR8 pathway 1. Experimental materials and equipment 1. HEK-Blue ^TM hTLR8 cells (Invivogen)
2. Resiquimod (R848/Resiquimod, Invivogen)
3. Basic phosphatase detection medium (Quanti-Blue Detection, Invivogen)
4. Blasticidin (Invivogen)
5. Bleomycin (Zeocin, Invivogen)
6. Neomycin (Normocin, Invivogen)
7. DMEM/High Glucose Medium (DMEM/HIGH Glucose, GE Healthcare)
8. Fetal bovine serum (FBS, Gibco)
9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)
10. Sterile pure water (homemade by Shanghai Hengrui)
11, 15 mL centrifuge tube (Corning)
12, 96-well combination plate (Corning)
13, 96-well flat bottom cell culture plate (Corning)
14. Thermoscientific cell incubator (Thermo scientific)
15. Temperature chamber (Shanghai Yicheng Scientific Instruments Co., Ltd.)
16, PHERAstar FS microplate reader (BMG Labtech)
2. Experimental Procedures HEK-Blue ^TM hTLR8 cells were purchased from Invivogen, and the cells were used to cotransfer the human Toll-like receptor 8 (TLR8) gene and secreted basic phosphatase-containing reporter gene (SEAP) into HEK293 cells. The basic phosphatase reporter gene (SEAP) is under the control of the IFN-β minimal promoter containing five NF-κB and AP-1 binding sites, and upon activation of TLR8 with agonists, downstream NF-κB and AP-1 binding sites are activated. SEAP secretion was triggered by kB and AP-1, and after addition of an antagonistic compound, the above pathway was inhibited and SEAP secretion was reduced, and the activity of compounds on the TLR8 pathway was evaluated by measuring OD620 with SEAP substrate. .

20 mM of test compound dissolved in 100% DMSO was stepped to 2000 μM, 400 μM, 80 μM, 16 μM, 3.2 μM, 0.64 μM, 0.128 μM, 0.0256 μM with 100% DMSO. After dilution, blank wells were made into 100% DMSO and diluted 20-fold in DMEM/high glucose medium (complete medium, hereinafter) containing 10% inactivated FBS. Resiquimod was diluted to 60 μM with sterile water. Place 60 μM of resiquimod diluted in sterile water at 20 μL/well in a 96-well cell culture plate, and add resiquimod at 20 μL per well of the compound diluted in the above complete medium and 100% DMSO. I put it in the well. Negative control wells received 20 μL of sterile water and 20 μL of 100% DMSO diluted in complete medium.

HEK-Blue ^™ hTLR8 cells were cultured in DMEM/high glucose medium containing 10% inactivated FBS, 100 μg/mL neomycin, 10 μg/mL blasticidin, and 100 μg/mL bleomycin. Take cells with good growth and 70% to 80% growth, discard the growth medium, wash the cells once by adding 5 mL to 10 mL of prewarmed PBS at 37 °C, and add 2 mL to 2 mL of prewarmed PBS. Add 5 mL, incubate at 37°C for 1 to 2 minutes, scatter the cells with a pipette, transfer the cells to a 15 mL centrifuge tube, count the cells, and bring the cell density to 4.8 with complete medium. The concentration was adjusted to ×10 ⁵ /mL. 160 μL of the cell suspension with adjusted density was placed in the above 96-well cell culture plate, and the final number of cells in each well was 76,500/well, the final concentration of resiquimod was 6 μM, and the final concentration of each test compound was 10,000. nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM. The cells were incubated in an incubator at 37°C and 5% _CO2 for 20 hours, then 20 μL of the supernatant was added to 180 μL of the prepared basic phosphatase detection medium and incubated in the dark in an incubator at 37°C. After incubation for 120 minutes, the absorbance value of OD620 was read using a microplate reader. The inhibition rate was calculated using the following formula:
Inhibition rate = {1 - (OD _{test compound} - OD _{negative control well} ) / (OD _{blank well} - OD _{negative control well} )} x 100%
An inhibition curve was drawn using Graphpad Prism software according to each concentration of the compound and the corresponding inhibition rate, and the IC ₅₀ value, which is the concentration of the compound at which the inhibition rate was 50%, was calculated as shown in Table 2.

Conclusion: The compounds according to the present disclosure have an inhibitory effect on the TLR8 pathway.

Test Example 3 Inhibitory effect of the compound according to the present disclosure on the human TLR9 activation pathway 1. Experimental materials and equipment 1. HEK-Blue ^TM hTLR9 cells (Invivogen)
2. CpG ODN2006 (Invivogen)
3. Basic phosphatase detection medium (Quanti-Blue Detection, Invivogen)
4. Blasticidin (Invivogen)
5. Bleomycin (Zeocin, Invivogen)
6. Neomycin (Normocin, Invivogen)
7. DMEM/High Glucose Medium (DMEM/HIGH Glucose, GE Healthcare)
8. Fetal bovine serum (FBS, Gibco)
9. Phosphate buffer (Shanghai Yuanpei Biotechnology Co., Ltd.)
10. Sterile pure water (homemade by Shanghai Hengrui)
11, 15 mL centrifuge tube (Corning)
12, 96-well combination plate (Corning)
13, 96-well flat bottom cell culture plate (Corning)
14. Thermoscientific cell incubator (Thermo scientific)
15. Temperature chamber (Shanghai Yicheng Scientific Instruments Co., Ltd.)
16, PHERAstar FS microplate reader (BMG Labtech)
2. Experimental Procedures HEK-Blue ^TM hTLR9 cells were purchased from Invivogen, and the cells were used to cotransfer the human Toll-like receptor 9 (TLR9) gene and the secreted basic phosphatase-containing reporter gene (SEAP) into HEK293 cells. The basic phosphatase reporter gene (SEAP) is under the control of the IFN-β minimal promoter containing five NF-κB and AP-1 binding sites, and upon activation of TLR9 with agonists, downstream NF-κB and AP-1 binding sites are activated. SEAP secretion was triggered by kB and AP-1, and after addition of an antagonistic compound, the above pathway was inhibited and SEAP secretion was reduced, and the activity of compounds on the TLR9 pathway was evaluated by measuring OD620 with SEAP substrate. .

20 mM of test compound dissolved in 100% DMSO was stepped to 2000 μM, 400 μM, 80 μM, 16 μM, 3.2 μM, 0.64 μM, 0.128 μM, 0.0256 μM with 100% DMSO. After dilution, blank wells were made into 100% DMSO and diluted 20-fold in DMEM/high glucose medium (complete medium, hereinafter) containing 10% inactivated FBS. CpG ODN2006 was diluted to 10 μM with sterile water. Add 10 μM of CpG ODN2006 diluted in sterile water at 20 μL/well to a 96-well cell culture plate and add CpG ODN2006 at 20 μL per well of the compound diluted in the above complete medium and 100% DMSO. into wells containing Negative control wells received 20 μL of sterile water and 20 μL of 100% DMSO diluted in complete medium.

HEK-Blue ^™ hTLR9 cells were cultured in DMEM/high glucose medium containing 10% FBS, 100 μg/mL neomycin, 10 μg/mL blasticidin, and 100 μg/mL bleomycin. Take cells with good growth and 70% to 80% growth, discard the growth medium, wash the cells once by adding 5 mL to 10 mL of prewarmed PBS at 37 °C, and add 2 mL to 2 mL of prewarmed PBS. Add 5 mL, incubate for 1-2 minutes at 37°C, spatter the cells with a pipette, transfer the cells to a 15 mL centrifuge tube, count the cells, and add 10% inactivated FBS. The cell density was adjusted to 4.8×10 ⁵ /mL with DMEM/high glucose medium containing DMEM/high glucose medium. 160 μL of the cell suspension with adjusted density was placed in the above 96-well cell culture plate, and the final number of cells in each well was 76,500/well, the final concentration of CpG ODN2006 was 1 μM, and the final concentration of the test compound was respectively They became 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, and 0.128 nM. The cells were incubated in an incubator at 37°C and 5% _CO2 for 20 hours, then 20 μL of the supernatant was added to 180 μL of the prepared basic phosphatase detection medium and incubated in the dark in an incubator at 37°C. After incubating for 15 minutes, the absorbance value at OD620 was read using a microplate reader. The inhibition rate was calculated using the following formula:
Inhibition rate = {1 - (OD _{test compound} - OD _{negative control well} ) / (OD _{blank well} - OD _{negative control well} )} x 100%
An inhibition curve was drawn using Graphpad Prism software according to each concentration of the compound and the corresponding inhibition rate, and the IC ₅₀ value, which is the concentration of the compound at which the inhibition rate was 50%, was calculated as shown in Table 3.

Conclusion: The compounds according to the present disclosure have an inhibitory effect on the TLR9 pathway.

Claims (24)

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,
One of these days,
Y is CR ^4a or a nitrogen atom,
Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
R ⁰ is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, -NR ^g R ^L , nitro group, hydroxy group, hydroxyalkyl group as well as
wherein the alkyl group is optionally an alkoxy group, a haloalkoxy group, a cyano group, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , a cycloalkyl group, a heterocyclyl group, an aryl group. and one or more substituents selected from heteroaryl groups,
L is selected from a chemical bond, NR ^L , an oxygen atom, a sulfur atom, and an alkylene group, where the alkylene group is optionally a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group. substituted with one or more substituents selected from groups, cyano groups, amino groups, nitro groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups,
R ^g and R ^L are the same or different, and each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. selected from
Ring C is selected from a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
Each R ¹ is the same or different, and each independently represents a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group and Heteroaryl groups each independently optionally include halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, Substituted with one or more substituents selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
^R2 is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group , an aryl group, and a heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with halogen. , alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group substituted with one or more selected substituents,
^R3 is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group , an aryl group, and a heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are each independently optionally substituted with halogen. , alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group substituted with one or more selected substituents,
Each R ⁴ is the same or different, and each independently represents a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an oxo group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group , nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, Aryl and heteroaryl groups each independently optionally include halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxy group. Substituted with one or more substituents selected from an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
R ^4a is selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, and a hydroxyalkyl group,
Each R ⁵ is the same or different, and each independently represents a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, oxo group, haloalkyl group, haloalkoxy group, cyano group, amino group , -NR ^c R ^d , selected from nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the alkyl group, alkenyl group, alkynyl group, alkoxy group, cyclo Alkyl, heterocyclyl, aryl and heteroaryl groups each independently optionally include halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino group, nitro group, hydroxy group, hydroxyalkyl group, -C(O)OR ⁶ , -C(O)NR ⁷ R ⁸ , -NR ⁷ R ⁸ , -S(O) ₂ R ⁹ , cycloalkyl group, heterocyclyl substituted with one or more substituents selected from groups, aryl groups and heteroaryl groups,
R ⁶ is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group,
R ^c , R ^d , R ⁷ and R ⁸ are the same or different, and each independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group , aryl group and heteroaryl group,
Alternatively, R ^c and R ^d together with the linked nitrogen atom form a heterocyclyl group, and the heterocyclyl group optionally includes a halogen, an alkyl group, an oxo group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, Substituted with one or more substituents selected from a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
Alternatively, R ⁷ and R ⁸ together with the linked nitrogen atom form a heterocyclyl group, and the heterocyclyl group optionally includes a halogen, an alkyl group, an oxo group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, Substituted with one or more substituents selected from a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
^R9 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group,
J is 0, 1 or 2,
k is 0, 1 or 2,
n is 0, 1, 2, 3 or 4,
s is 0, 1, 2, 3 or 4, and t is 0, 1, 2, 3 or 4,
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. A compound represented by general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, that is,
One of these days,
Rings A, R ⁰ , R ¹ to R ⁴ , R ^4a , J, k, n and s are as defined in claim 1,
A compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. A compound represented by general formula (IIG) or general formula (IV) or a pharmaceutically acceptable salt thereof, that is,
One of these days,
Ring A, ring C, L, R ¹ -R ⁵ , R ^4a , J, k, n, s and t are as defined in claim 1,
A compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, preferably, Ring A is a pyridyl group or
and more preferably, ring A is a pyridyl group,
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3. J is 0 or 1 and k is 1 or 2, preferably J is 1 and k is 1,
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4. R ⁰ is a hydrogen atom, a C _1-6 alkyl group, -NR ^g R ^L and
wherein said C _1-6 alkyl group is optionally substituted with one or more -C(O)NR ⁷ R ⁸ ;
L, ring C, R ⁵ , R ⁷ , R ⁸ , R ^g , R ^L and t are as defined in claim 1,
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 and 4 to 5. L is NR ^L or a C _1-6 alkylene group, R ^L is a hydrogen atom or a C _1-6 alkyl group, and/or ring C is a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group,
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6. Each R ¹ is the same or different, and each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7. R ² is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8. R ³ is selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group,
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9. Each R ⁴ is the same or different, and each independently represents a hydrogen atom or a C _1-6 alkyl group,
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10. Each R ⁵ is the same or different, and each independently represents a hydrogen atom, a halogen, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, -NR ^c R ^d , and a 3- to 12-membered selected from heterocyclyl groups, R ^c and R ^d are the same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, and a 3- to 12-membered heterocyclyl group,
A compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof. Any one compound selected from
A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12. A compound represented by general formula (IIA) or (IVA) or a pharmaceutically acceptable salt thereof, that is,
One of these days,
Ring A, R ¹ to R ⁴ , R ^4a , R ^L , J, k, n and s are as defined in claim 1,
A compound represented by general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. A compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof,
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
Rings A, R ¹ to R ⁴ , J, k, n and s are as defined in claim 1,
A compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof. Any one compound selected from
A compound or a pharmaceutically acceptable salt thereof. A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising:
A compound of general formula (IIA) or a pharmaceutically acceptable salt thereof is subjected to a nucleophilic substitution reaction with R ⁰ -X to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof. ,
One of these days,
X is a leaving group, preferably halogen, more preferably bromine or iodine,
^R0 is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a haloalkyl group, a hydroxyalkyl group, and
wherein the alkyl group is optionally an alkoxy group, a haloalkoxy group, a cyano group, -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , a cycloalkyl group, a heterocyclyl group, an aryl group. and a heteroaryl group, preferably R ⁰ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a haloalkyl group, a hydroxyalkyl group, and
selected from
L is a chemical bond or an alkylene group, where the alkylene group optionally includes a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group. , hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group,
Ring A, Ring C, R ¹ to R ⁵ , n, s, t, J and k are as defined in claim 2,
Method. A method for preparing a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof, comprising:
Removing the protecting group R ^w from the compound of general formula (IIB) or a pharmaceutically acceptable salt thereof to obtain a compound of general formula (IIA) or a pharmaceutically acceptable salt thereof,
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
Ring A, R ¹ to R ⁴ , n, s, J and k are as defined in claim 14,
Method. A method for preparing a compound represented by general formula (IIB) or a pharmaceutically acceptable salt thereof, comprising:
A compound of general formula (IIa) or a pharmaceutically acceptable salt thereof is reacted with a compound of general formula (IIbb) using Larock indole synthesis to obtain a compound of general formula (IIB) or a pharmaceutically acceptable salt thereof. including,
One of these days,
R ^w is an amino protecting group, preferably a tert-butoxycarbonyl group,
R ^t is halogen, preferably bromine;
Ring A, R ¹ to R ⁴ , n, s, J and k are as defined in claim 15,
Method. A compound represented by general formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents or A pharmaceutical composition comprising an excipient. Inhibition of TLR7, TLR8 or TLR9 by the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 20 Use in the preparation of a medicament for inhibiting TLR7, preferably use in the preparation of a medicament for inhibiting TLR7 and TLR8, or use in the preparation of a medicament for inhibiting TLR7 and TLR9. Use in preparation. Inhibition of TLR7, TLR8 and TLR9 by the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 20 Use in the preparation of drugs for. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 20 can be used to treat inflammatory or autoimmune diseases. Use in the preparation of therapeutic and/or prophylactic medicaments. The inflammatory or autoimmune disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Sjögren's syndrome,
Use according to claim 23.